Fulvestrant formulations and methods of their use

ABSTRACT

The disclosure is directed to fulvestrant formulations including suspensions of fulvestrant particles suitable for injection. The formulations can comprise fulvestrant particles having an LD Dv(10) less than about 3 microns, for example, between about 1 micron to about 3 microns, an LD Dv(50) less than about 35 microns, for example, between about 2 microns and about 35 microns, and an LD Dv(90) less than about 120 microns, for example, between about 4 microns and about 120 microns. The formulations can comprise fulvestrant particles having a CE Dv(90) less than about 200 microns, for example, between about 10 microns and about 200 microns, a CE Dv(50) less than about 60 microns, for example, between about 5 microns and about 60 microns, and a CE Dv(10) less than about 25 microns, for example, between about 1 micron and about 25 microns.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/332,842, filed May 6, 2016, and U.S. Provisional Application No.62/420,555, filed Nov. 10, 2016, the entireties of which areincorporated by reference herein.

FIELD

The disclosure is directed to fulvestrant-containing formulations andmethods of their use in the treatment of disease.

BACKGROUND

Fulvestrant, or7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)estra-1,3,5(10)-triene-3,17-diol,has the structure of formula (1):

Fulvestrant is a selective estrogen receptor degrader (SERD) indicatedfor the treatment of hormone receptor positive metastatic breast cancerin postmenopausal women with disease progression following anti-estrogentherapy.

As with other steroidal-like compounds, fulvestrant has physicalproperties which make preparing fulvestrant pharmaceutical compositionsdifficult. Fulvestrant is a particularly lipophilic molecule, even whencompared with other steroidal compounds, and its aqueous solubility isextremely low.

Due to the poor solubility and oral bioavailability of fulvestrant, thedrug is currently administered via intramuscular injection of anoil-based fulvestrant formulation. The current commercial formulation offulvestrant, FASLODEX™, is dosed at 500 mg and requires that two 5 mLinjections of a 50 mg/mL fulvestrant formulation be administeredintramuscularly. Each 5 mL injection contains 10% w/v alcohol, 10% w/vbenzyl alcohol, and 15% w/v benzyl benzoate as co-solvents and made upto 100% w/v with castor oil as a further co-solvent and release ratemodifier. Administration of the formulation is slow (1-2 minutes perinjection) and painful, due to the viscous oil-based vehicle used tosolubilize fulvestrant. A warning has been added to the FASLODEX™ labelconcerning painful injections, sciatica, neuropathic pain, andperipheral neuropathy.

It has been previously reported (U.S. Pat. No. 6,774,122 to AstraZeneca)that intra-muscular injections of fulvestrant in the form of an aqueoussuspension were not suitable for use. Those suspensions resulted inextensive local tissue irritation at the injection site as well as apoor release profile due to the presence of fulvestrant in the form ofsolid particles. Furthermore, the fulvestrant release rate was reportedas not clinically significant.

There is a need for fulvestrant formulations with improved dosingproperties. The disclosure is directed to these and other importantneeds.

SUMMARY

The present disclosure provides formulations comprising fulvestrantparticles. The disclosure also provides fulvestrant suspensions,preferably those having a fulvestrant concentration of equal to orgreater than about 50 mg/mL. The disclosure also provides formulationscomprising fulvestrant particles and a non-oil vehicle. Some aspects ofthe disclosure are directed to pharmaceutical compositions comprisingfulvestrant particles having an LD Dv(90) greater than or equal to about7 microns. Further aspects of the disclosure are directed topharmaceutical compositions comprising fulvestrant particles having a CEDv(90) less than about 200 microns, for example, between about 10microns and about 200 microns, a CE Dv(50) less than about 60 microns,for example, between about 5 microns and about 60 microns, and a CEDv(10) less than 25 microns, for example, between about 1 microns andabout 25 microns. Other aspects of the disclosure are directed topharmaceutical compositions comprising fulvestrant at a concentration ofabout 100 mg/mL, whereupon administration to a subject, the 90%confidence intervals (CI) of the relative mean AUC_((0-t)), relativemean AUC_((0-∞)), or both of the pharmaceutical compositions of thedisclosure is within 80% to 125% of the relative mean AUC_((0-t)) andrelative mean AUC_((0-∞)), respectively, of a reference listedfulvestrant product. Other aspects of the disclosure are directed tofulvestrant formulations having a concentration of about 100 mg/mL andparticular pharmacokinetic profiles. In other aspects, the disclosure isdirected to pharmaceutical compositions comprising fulvestrantparticles, wherein the fulvestrant concentration is about 40 to 125mg/mL.

Methods of making and using the products described herein are alsodescribed.

BRIEF DESCRIPTION OF THE DRAWINGS

The summary, as well as the following detailed description, is furtherunderstood when read in conjunction with the appended drawings. For thepurpose of illustrating the disclosure, there are shown in the drawingsexemplary embodiments of the disclosure; however, the disclosure is notlimited to the specific methods, compositions, and devices disclosed. Inthe drawings:

FIG. 1A depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines;

FIG. 1B depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines;

FIG. 2A depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines;

FIG. 2B depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines;

FIG. 2C depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines;

FIG. 3 depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines;

FIG. 4 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 5 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 6 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 7 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 8 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 9 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 10 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 11 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 12 depicts aspects of exemplary methods of preparation forfulvestrant suspensions of the present disclosure;

FIG. 13 depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines;

FIG. 14 depicts pharmacokinetic data for administration of commercialfulvestrant formulations (FASLODEX™) and some exemplary fulvestrantformulations of the present disclosure to canines; and

FIG. 15 depicts schematic representations of aspects of methods ofpreparation of some exemplary fulvestrant formulations of the presentdisclosure.

All callouts and annotations in the Figures are hereby incorporated intothis description as if fully set forth herein.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present disclosure may be understood more readily by reference tothe following detailed description taken in connection with theaccompanying figures and examples, which form a part of this disclosure.It is to be understood that this disclosure is not limited to thespecific devices, methods, applications, conditions or parametersdescribed and/or shown herein, and that the terminology used herein isfor the purpose of describing particular embodiments by way of exampleonly and is not intended to be limiting of the claimed disclosure.

As used in the specification including the appended claims, the singularforms “a,” “an,” and “the” include the plural, and reference to aparticular numerical value includes at least that particular value,unless the context clearly dictates otherwise.

When a range of values is expressed, another embodiment includes fromthe one particular value and/or to the other particular value. Allranges are inclusive and combinable. Further, reference to values statedin ranges include each and every value within that range. When valuesare expressed as approximations, by use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.The term “about” as used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, is meant toencompass reasonable variations of the value, such as, for example, ±10%from the specified value. For example, the phrase “about 50%” caninclude ±10% of 50, or from 45% to 55%.

It is to be appreciated that certain features of the disclosure whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.Conversely, various features of the disclosure that are, for brevity,described in the context of a single embodiment, may also be providedseparately or in any subcombination.

Terms

As used herein, whether by itself or in conjunction with another term orterms, it should be understood that the phrases “method of treating” and“method of treatment” may be used interchangeably with the phrase “foruse in the treatment of” a particular disease.

As used herein, whether by itself or in conjunction with another term orterms, “pharmaceutically acceptable” indicates that the designatedentity such as, for example, e.g., a pharmaceutically acceptableexcipient is generally chemically and/or physically compatible withother ingredients in a formulation, and/or is generally physiologicallycompatible with the recipient thereof.

As used herein, “pharmaceutical composition” refers to a formulation asdescribed herein that includes one or more pharmaceutically acceptableexcipients, that is suitable for administration to a subject. It shouldbe understood that the term “pharmaceutical composition” encompasses (a)suspensions and (b) suspensions which have been dried such that one ormore solvents have been removed partially or completely, either byevaporation or sublimation, including, but not limited to, lyophilizedcakes.

As used herein, whether by themselves or in conjunction with anotherterm or terms, “subject(s),” “individual(s),” and “patient(s)”, refer tomammals, including humans. The term human(s) refers to and includes, ahuman child, adolescent, or adult.

As used herein, whether by themselves or in conjunction with anotherterm or terms, “treats,” “treating,” “treated,” and “treatment,” referto and include ameliorative, palliative, and/or curative uses andresults, or any combination thereof. In other embodiments, the methodsdescribed herein can be used prophylactically. It should be understoodthat “prophylaxis” or a prophylactic use or result do not refer to norrequire absolute or total prevention (i.e., a 100% preventative orprotective use or result). As used herein, prophylaxis or a prophylacticuse or result refer to uses and results in which administration of acompound or formulation diminishes or reduces the severity of aparticular condition, symptom, disorder, or disease described herein;diminishes or reduces the likelihood of experiencing a particularcondition, symptom, disorder, or disease described herein; or delays theonset or relapse (reoccurrence) of a particular condition, symptom,disorder, or disease described herein; or any combination of theforegoing.

As used herein, whether used alone or in conjunction with another termor terms, “therapeutic” and “therapeutically effective amount”, refer toan amount of a compound or formulation that (a) treats a particularcondition, symptom, disorder, or disease described herein; (b)attenuates, ameliorates or eliminates one or more symptoms of aparticular condition, disorder, or disease described herein; (c) delaysthe onset or relapse (reoccurrence) of a particular condition, symptom,disorder, or disease described herein. It should be understood that theterms “therapeutic” and “therapeutically effective” encompass any one ofthe aforementioned effects (a)-(c), either alone or in combination withany of the others (a)-(c).

As used herein, whether used alone or in conjunction with another termor terms, “therapeutic agent” refers to any substance included in aformulation that is useful in the treatment of a disease, condition, ordisorder or comorbidity (i.e., a disease, condition, or disorder thatexists simultaneously with breast cancer) and is not fulvestrant.

As used herein, whether used alone or in conjunction with another termor terms, “suspension” refers to solid particles dispersed in a liquidvehicle.

As used herein, whether used alone or in conjunction with another termor terms, “formulation” refers to a mixture of components. The term“formulation” encompasses pharmaceutical compositions, and suspensions,as well as suspensions that have been dried such that one or moresolvents have been removed partially or completely (e.g., lyophilizedcakes).

As used herein “Dv(10)”, “Dv(50)” and “Dv(90)” are defined as the volumeweighted particle diameters where a cumulative 10%, 50% or 90% v/v ofthe particles have an equal or smaller diameter, respectively, whenmeasured. For example, if a particle population has a Dv(50) of about 25microns, 50% of the particles in volume have a diameter of less than orequal to about 25 microns.

As used herein, Dn(10)”, “Dn(50)” and “Dn(90)” are defined as the numberweighted particle diameters where a cumulative 10%, 50% or 90% of theparticles have an equal or smaller diameter, respectively, whenmeasured. For example, if a particle population has a Dn(50) of about 25microns, 50% of the particles in number have a diameter of less than orequal to about 25 microns.

Particle size and particle size distributions can be determined bymeasurement via laser diffraction. Particle size analysis by laserdiffraction methods is known in the art and is explained more fully byISO 13320:2009(E), “Particle size analysis—Laser diffraction methods,”International Organization for Standardization which is incorporated byreference herein in its entirety for all purposes. Particle sizesdetermined by laser diffraction are represented as the diameter of asphere having equivalent volume to the particle volume as determined byMie theory of light scattering. Tables 1-7 and 23-27 and FIGS. 4-12provide laser diffraction particle size and particle size distribution(“PSD”) data for some exemplary embodiments of the present invention,with measurements taken during methods of preparation, on the day offormulation (“Day 0”), and at various later dates after formulation, asindicated. Measurements were taken “as is” and “sonicated.” Data for“sonicated” samples indicates that the measurement sample was subjectedto sonication to disperse agglomerates and provide stable repeatmeasurements, as more fully described in ISO 13320:2009(E). Valuesmeasured via laser diffraction are indicated as such in the Figures andTables, or are referred to herein by “laser diffraction Dv(##)”, “LDDv(##)”, “laser diffraction diameter”, or “LD diameter.”

Particle size and particle size distributions can also be determined bymicroscopy image capture and analysis. Microscopy image capture andanalysis captures a two dimensional (2D) image of a 3D particle andcalculates various size and shape parameters from the 2D image. Particlesizes determined by microscopy image capture and analysis arerepresented as the diameter of a circle with the equivalent area as the2D image of the particle, referred to herein as a circle equivalent or“CE” diameter. Particle size analysis by microscopy image capture andanalysis is known in the art and is explained more fully by ISO13322-1:2014, “Particle size analysis—Image analysis methods—Part 1:Static image analysis methods,” International Organization forStandardization, which is incorporated by reference herein in itsentirety for all purposes. Values measured by microscopy image captureand analysis are referred to herein by “circle equivalent diameter,” “CEdiameter,” “circle equivalent Dv(##),” “CE Dv(##)”, or “CE Dn(##)”.Tables 41-50 provide microscopy image capture and analysis particle sizeand particle size distribution data for some exemplary embodiments ofthe present invention, with measurement samples taken during methods ofpreparation, after an initial suspension is formed, or afterlyophilization and reconstitution, as indicated.

A. Formulations. Suspensions Comprising Fulvestrant Particles and aVehicle

In particular embodiments, the invention is directed to suspensionscomprising fulvestrant particles and a vehicle. The fulvestrantparticles may have different particle size distributions as describedmore fully elsewhere herein. As used herein, a “vehicle” is a suspendingmedium, preferably a pharmaceutically acceptable suspending medium. Incertain embodiments, the vehicle is a non-oil vehicle. As used herein,“oils” are non-polar substances that have no or low miscibility withwater. Castor oil is an example of an oil. In other embodiments of theinvention, the vehicle comprises water, i.e., is aqueous. As usedherein, an “aqueous” vehicle is a vehicle that comprises at least about50% w/w water. In some embodiments, the aqueous vehicle comprises atleast about 60% w/w, at least about 70% w/w, at least about 80% w/w, atleast about 85% w/w, at least about 90% w/w, at least about 95% w/w, atleast about 96% w/w, at least about 97% w/w, at least about 98% w/w, orat least about 99% w/w water. In certain embodiments of the invention,the vehicle is water. In yet other embodiments of the invention, thevehicle is a non-aqueous medium. In some embodiments, a vehiclecomprises a single suspending medium. In other embodiments, a vehiclecomprises a mixture of two or more suspending mediums, which may beaqueous or non-aqueous. In still other embodiments of the invention, thevehicle comprises both water and a non-aqueous solvent. In particularembodiments of the invention, the suspension is substantially oil-free.As used herein, a “substantially oil-free” suspension is a suspensioncomprising a vehicle that comprises at most about 10% w/w oil. In somepreferred embodiments, a substantially oil-free suspension comprises avehicle that comprises less than about 5% w/w oil, less than about 2%w/w oil, less than about 1% w/w oil, less than about 0.5% w/w oil, lessthan about 0.1% w/w oil, or comprises a vehicle that is free of oil.

Fulvestrant suspensions of the disclosure can have fulvestrant presentat a concentration of about 40 mg/mL to about 125 mg/mL in a vehicle.The fulvestrant present in the fulvestrant suspensions may havedifferent particle size distributions as described more fully elsewhereherein. In particular embodiments of the invention, fulvestrant ispresent at a concentration equal to or greater than about 40 mg/mL. Infurther embodiments, fulvestrant is present at a concentration of about40 to about 75 mg/mL. In other embodiments, fulvestrant is present at aconcentration of about 75 mg/mL to about 125 mg/mL. In still furtherembodiments, fulvestrant is present at a concentration of about 40mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL,about 65 mg/mL, about 70 mg/mL, or about 75 mg/mL.

In certain embodiments, fulvestrant is present in the suspension at aconcentration equal to or greater than about 75 mg/mL. In furtherembodiments, fulvestrant is present in the suspension at a concentrationof about 75 to about 125 mg/mL. In particular embodiments, fulvestrantis present in the suspension at a concentration of about 80 mg/mL, about85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 105mg/mL, about 110 mg/mL, about 115 mg/mL, about 120 mg/mL, or about 125mg/mL. In other embodiments, fulvestrant is present in the suspension ata concentration of about 75 mg/mL to about 95 mg/mL, about 80 mg/mL toabout 100 mg/mL, about 90 mg/mL to about 110 mg/ml, about 95 mg/mL toabout 105 mg/mL, about 95 mg/mL to about 115 mg/mL, about 100 mg/mL toabout 110 mg/mL, about 110 mg/mL to about 125 mg/mL, including allranges and subranges there between.

Pharmaceutical Compositions Comprising Fulvestrant

Other embodiments of the disclosure include pharmaceutical compositionscomprising fulvestrant. These pharmaceutical compositions may beprepared by combining fulvestrant, as described herein, with one or moreadditional excipients, preferably pharmaceutically acceptableexcipients.

In certain embodiments, the pharmaceutical compositions may furthercomprise a stabilizer, or one or more stabilizers, or two or morestabilizers. In still further embodiments of the invention, thestabilizer is selected from the group consisting of surfactants,polymers, cross-linked polymers, buffering agents, electrolytes, andnon-electrolytes. In yet further embodiments of the invention, thepharmaceutical composition comprises a combination of two or morestabilizers selected from the group consisting of surfactants, polymers,cross-linked polymers, buffering agents, electrolytes, andnon-electrolytes.

In certain embodiments of the invention, the pharmaceutical compositionscomprising fulvestrant comprise about 0.2 mg/mL to about 75 mg/mL of oneor more stabilizers, and all ranges and subranges therebetween. Inparticular embodiments of the invention, the pharmaceutical compositioncomprises about 0.2 to 0.7 mg/mL, 0.5 to 1 mg/mL, 1 to 5 mg/mL, 2 to 8mg/mL, 5 to 6 mg/mL, 5 to 10 mg/mL, 8 to 12 mg/mL, 10 to 15 mg/mL, 15 to20 mg/mL, 20 to 30 mg/mL, 30 to 40 mg/mL, 40 to 50 mg/mL, 45 to 55mg/mL, 50 to 60 mg/mL, or 60 to 75 mg/mL of one or more stabilizers, andall ranges and subranges there between. In further embodiments of theinvention, the pharmaceutical composition comprises about 0.2 mg/mL, 0.5mg/mL, 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 5.5 mg/mL, 6 mg/mL,7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 12 mg/mL, 15 mg/mL, 17 mg/mL, 20mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55mg/mL, 60 mg/mL, 65 mg/mL, 70 mg/mL, or about 75 mg/mL of one or morestabilizers.

In yet further embodiments of the invention, the stabilizer is asurfactant. For example, the stabilizer can be, but is not limited to,polyethylene oxide (PEO), a PEO derivative, polysorbate 80, polysorbate20, poloxamer 188 (including, but not limited to, PLURONIC® F-68poloxamer sold by BASF Corp. (Wyandotte, Mich., USA)), poloxamer 124(including, but not limited to, PLURONIC® L44 poloxamer sold by BASFCorp. (Wyandotte, Mich., USA)), poloxamer 407 (including, but notlimited to, PLURONIC® F127 poloxamer sold by BASF Corp. (Wyandotte,Mich., USA)), polyethoxylated vegetable oils, polyethoxylated castor oil(including but not limited to KOLLIPHOR® EL, formerly known asCREMOPHOR® EL sold by BASF Corp. (Wyandotte, Mich., USA)), sorbitanpalmitate (including, but not limited to, SPAN™ 40 sold by CrodaInternational Plc), lecithin, poly(vinyl alcohol) (“PVA”), human serumalbumin, and mixtures thereof.

In particular embodiments of the invention, the stabilizer is a polymer.For example, the stabilizer can be, but is not limited to, apolyvinylpyrrolidone (“PVP”) (such as, but not limited to povidone K12,povidone K17, PLASDONE™ C-12 povidone, PLASDONE™ C-17 povidone,PLASDONE™ C-30 povidone, and mixtures thereof), polyethylene glycol3350, and mixtures thereof.

In other embodiments of the invention, the stabilizer is an electrolyte,i.e., a salt that dissociates into anions and cations in aqueoussolution. For example, the stabilizer can be, but is not limited to,sodium chloride, calcium chloride, and mixtures thereof.

In still other embodiments of the invention, the stabilizer is anon-electrolyte, i.e., is non-ionic. For example, the stabilizer can be,but is not limited to, dextrose, glycerol (also referred to asglycerin), mannitol, or mixtures thereof.

In other embodiments of the invention, the stabilizer is a cross-linkedpolymer. For example, the stabilizer can be, but is not limited to,carboxymethylcellulose sodium (CMC). In some embodiments of theinvention, the stabilizer is CMC 7LF, CMC 7MF, CMC 7HF, or mixturesthereof.

In other embodiments of the invention, the stabilizer is a bufferingagent, for example, NaH₂PO₄.H₂O, NaH₂PO₄.2H₂O, anhydrous NaH₂PO₄, sodiumcitrate, citric acid, Tris, sodium hydroxide, HCl, or mixtures thereof.

In further embodiments of the invention, combinations of non-electrolytestabilizers and electrolyte stabilizers may be used. In someembodiments, the combination of stabilizers may comprise two or morenon-electrolyte stabilizers. In other embodiments, the combination ofstabilizers may comprise two or more electrolyte stabilizers. In furtherembodiments, the combination of stabilizers may comprise one or morenon-electrolyte stabilizers and one or more electrolyte stabilizers. Inyet further embodiments, the combination of stabilizers may comprise twoor more of mannitol, dextrose, and sodium chloride.

In certain embodiments of the invention, combinations of surfactantstabilizers and polymer stabilizers may be used. In some embodiments,the combination of stabilizers may comprise two or more surfactantstabilizers. In other embodiments, the combination of stabilizers maycomprise two or more polymer stabilizers. In further embodiments, thecombination of stabilizers may comprise one or more surfactantstabilizers and one or more polymer stabilizers. In yet furtherembodiments, the combination of stabilizers may comprise two or more ofpolysorbate 80, polysorbate 20, and poloxamer 188. In still furtherembodiments, the combination of stabilizers may comprise one or more ofpolysorbate 80, polysorbate 20, and poloxamer 188 and one or more ofpovidone K12, povidone K17, PLASDONE™ C-12 povidone, PLASDONE™ C-17povidone, PLASDONE™ C-30 povidone, and polyethylene glycol 3350. In yetstill further embodiments, the combination of stabilizers may comprisepolysorbate 80 and one or more of PLASDONE™ C-12 povidone and povidoneK12.

In certain embodiments, the pharmaceutical compositions comprisingfulvestrant comprise CMC (carboxymethylcellulose sodium). In someembodiments, the CMC is prepared and heat sterilized before beingcombined with the fulvestrant during methods of preparation (describedmore fully elsewhere herein). In further embodiments of the invention,the viscosity of a CMC solution can be modulated by the degree ofheating applied, which can allow for the formation of a plurality offulvestrant pharmaceutical compositions having identical constituents,but with different viscosity values. These different viscosity valuescan affect the physical stability of the fulvestrant pharmaceuticalcompositions and the pharmacokinetic characteristics upon administrationto subjects. In some embodiments, fulvestrant pharmaceuticalcompositions comprising CMC may be prepared in two or more parts witheach part comprising a different amount of CMC. In other embodiments oneor more such parts may be a suspension free of any CMC. In furtherembodiments, the parts can be mixed in an appropriate ratio to obtain adesired pharmaceutical composition.

In certain embodiments of the invention, the pharmaceutical compositionsin the form of liquid suspensions comprising fulvestrant and one or morestabilizers may exhibit different sedimentation behaviors to form eitherflocculated or caked suspension upon storage. In some embodiments of theinvention, after being stored, pharmaceutical compositions in the formof liquid suspensions comprising fulvestrant can be redispersed backinto a homogeneous suspension with an acceptable particle sizedistribution upon redispersion. Exemplary liquid suspension formulationsdescribed herein were prepared and tested for sedimentation andredispersion. The tested formulations exhibited different sedimentationbehaviors, but all were redispersible back to an acceptable, homogeneoussuspension after a 3-month storage period at room temperature.

In certain embodiments of the invention, the pharmaceutical compositionscomprising fulvestrant have a pH of from about 3-10, for example, about3, 4, 5, 6, 7, 8, 9, or about 10. In further embodiments of theinvention, the pharmaceutical composition has a pH of from about 5-8. Infurther embodiments of the invention, the pharmaceutical composition hasa pH of from about 6-8. In further embodiments of the invention, thepharmaceutical composition has a pH of from about 3-7. In certainembodiments of the invention, the pharmaceutical composition has a pH ofabout 6.0 to 8.0. In particular embodiments of the invention, thepharmaceutical composition has a pH of about 6.0 to 7.0, 6.5 to 7.0, 6.5to 7.5, 6.7 to 7.2, 7.0 to 7.2, 7.0 to 7.5, or 7.0 to 8.0. In furtherembodiments of the invention, the pharmaceutical composition has a pH ofabout 7.0.

In particular embodiments of the invention, the pharmaceuticalcomposition further comprises one or more buffering agents, i.e., anagent that when added to a pharmaceutical composition, results in apharmaceutical composition that resists pH changes or that results in achange in pH, such as, but not limited to, NaH₂PO₄.H₂O, NaH₂PO₄.2H₂O,anhydrous NaH₂PO₄, sodium citrate, citric acid, Tris, sodium hydroxide,HCl, or mixtures thereof. In certain embodiments of the invention, thepharmaceutical composition comprises about 1 mM to 20 mM, of one or morebuffering agents, and all ranges and subranges therebetween. Inparticular embodiments of the invention, the pharmaceutical compositioncomprises about 1 to 2 mM, 1 to 3 mM, 1 to 5 mM, 2 to 8 mM, 5 to 6 mM, 5to 10 mM, 8 to 12 mM, 10 to 15 mM, or 15 to 20 mM of one or morebuffering agents, and all ranges and subranges there between. In furtherembodiments of the invention, the pharmaceutical composition comprisesabout 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM ofone or more buffering agents.

In certain embodiments of the invention, the pharmaceutical compositionhas an osmolarity from about 280 mOsm/L to about 310 mOsm/L, forexample, about 280, 285, 290, 300, 305, or about 310 mOsm/L. In furtherembodiments of the invention, the pharmaceutical composition has anosmolarity from about 290 mOsm/L to about 300 mOsm/L. In yet furtherembodiments of the invention, the pharmaceutical composition has anosmolarity of about 290 mOsm/L. In some embodiments, the osmolarity maybe selected through the use of appropriate amounts of the one or morestabilizers, e.g., stabilizers that also act as tonicifiers, such as,but not limited to, the non-electrolyte stabilizers and electrolytestabilizers described herein. In some embodiments, the osmolarity may beselected through the use of appropriate amounts of one or more bufferingagents that act as tonicifiers in a pharmaceutical composition, such as,but not limited to, the buffering agents described herein.

In certain embodiments of the invention, the pharmaceutical compositionhas an absolute viscosity measured at 25° C. from about 1.0 cP to about1000 cP, and all ranges and subranges therebetween. In particularembodiments of the invention, the pharmaceutical composition has anabsolute viscosity measured at 25° C. from about 750 cP to about 1000cP, about 500 to about 750 cP, about 250 cP to about 500 cP, about 100cP to about 250 cP, about 50 cP to about 100 cP, about 25 cP to about 50cP, about 10 cP to about 25 cP, about 1 cP to about 10 cP, about 1 cP toabout 5 cP, about 1.0 cP to about 4.0 cP, about 1.0 cP to about 3.0 cP,about 1.0 cP to about 2.5 cP, about 1.0 cP to about 2.0 cP, about 1.5 cPto about 2.0 cP. In further embodiments of the invention, thepharmaceutical composition has an absolute viscosity measured at 25° C.of about 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP,1.8 cP, 1.9 cP, 2.0 cP, 2.1 cP, 2.2 cP, 2.3 cP, 2.4 cP, 2.5 cP, 2.6 cP,2.7 cP, 2.8 cP, 2.9 cP, 3.0 cP, 3.5 cP, 4.0 cP, 4.5 cP, 5.0 cP, 10 cP,15 cP, or 20 cP.

In yet further embodiments of the invention, pharmaceutical compositionshaving a fulvestrant concentration of 50 mg/mL or 100 mg/mL have anabsolute viscosity measured at 25° C. that is from about 2-fold to about500-fold lower than FASLODEX™, and all ranges and subrangestherebetween. In further embodiments of the invention, fulvestrantpharmaceutical compositions having a fulvestrant concentration of 50mg/mL or 100 mg/mL have an absolute viscosity measured at 25° C. that is500-fold lower, about 400-fold lower, about 300-fold lower, about250-fold lower, about 200-fold lower, about 150-fold lower, about100-fold lower, about 50-fold lower, about 40-fold lower, about 30-foldlower, about 20-fold lower, about 10-fold lower, about 5-fold lower,about 4-fold lower, about 3-fold lower, about 2-fold lower, or about1.5-fold lower than FASLODEX™. In further embodiments of the invention,for example, fulvestrant pharmaceutical compositions having afulvestrant concentration of 50 mg/mL or 100 mg/mL, have an absoluteviscosity measured at 25° C. that is substantially equivalent toFASLODEX™. Table 21 provides density measurements of some exemplaryfulvestrant pharmaceutical compositions of the present disclosure. Table22 provides viscosity measurements of some exemplary fulvestrantpharmaceutical compositions of the present disclosure.

In certain embodiments of the invention, the pharmaceutical compositioncomprises one or more additional pharmaceutically acceptable excipients.As used herein, a pharmaceutically acceptable excipient is generallychemically and/or physically compatible with other ingredients in apharmaceutical composition or pharmaceutical composition, and/or isgenerally physiologically compatible with the recipient thereof. In someembodiments, the one or more additional pharmaceutically acceptableexcipients are selected from the group consisting of preservatives,antioxidants, or mixtures thereof. In yet further embodiments of theinvention, the additional pharmaceutically acceptable excipient is apreservative such as, but not limited to, phenol, cresol,p-hydroxybenzoic ester, chlorobutanol, or mixtures thereof. In yetfurther embodiments of the invention, the additional pharmaceuticallyacceptable excipient is an antioxidant such as, but not limited to,ascorbic acid, sodium pyrosulfite, palmitic acid, butylatedhydroxyanisole, butylated hydroxytoluene, tocopherols, or mixturesthereof.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5.8 mg/mL of one or morestabilizers, and water for injection (WFI) q.s. to volume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5 mg/mL of one or moresurfactants, about 0.8 mg/mL of one or more polymers, and WFI q.s. tovolume.

In yet further embodiments of the invention, the pharmaceuticalcomposition comprises about 50 mg/mL fulvestrant, about 5 mg/mL ofpolysorbate 80, about 0.8 mg/mL of povidone K12 (PVP 12K), and WFI q.s.to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5.8 mg/mL of one or morestabilizers, about 9 mg/mL of one or more electrolytes, about 10 mM ofone or more buffering agents, and WFI q.s. to volume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5 mg/mL of one or moresurfactants, about 0.8 mg/mL of one or more polymers, about 9 mg/mL ofsodium chloride, about 10 mM of one or more of NaH₂PO₄.H₂O,NaH₂PO₄.2H₂O, and anhydrous NaH₂PO₄ (preferably a mixture of about 0.61mg/mL NaH₂PO₄.2H₂O and about 0.85 mg/mL of anhydrous NaH₂PO₄), and WFIq.s. to volume

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 55 mg/mL of one or morestabilizers, and WFI q.s. to volume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5 mg/mL of one or moresurfactants, about 50 mg/mL of one or more non-electrolytes, and WFIq.s. to volume.

In yet further embodiments of the invention, the pharmaceuticalcomposition comprises about 50 mg/mL fulvestrant, about 5 mg/mL ofpolysorbate 80, about 50 mg/mL of dextrose, and WFI q.s. to volume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,about 50 mg/mL of mannitol, and WFI q.s. to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5 mg/mL of one or morestabilizers, about 9 mg/mL of one or more electrolytes, and WFI q.s. tovolume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 50 mg/mL fulvestrant, about 5 mg/mL of one or moresurfactants, about 9 mg/mL of sodium chloride, and WFI q.s. to volume.

In yet further embodiments of the invention, the pharmaceuticalcomposition comprises about 50 mg/mL fulvestrant, about 5 mg/mL ofpolysorbate 80, about 9 mg/mL of sodium chloride, and WFI q.s. tovolume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 55 mg/mL of one or morestabilizers, and WFI q.s. to volume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of one or moresurfactants, about 50 mg/mL of one or more non-electrolytes, and WFIq.s. to volume.

In yet further embodiments of the invention, the pharmaceuticalcomposition comprises about 100 mg/mL fulvestrant, about 5 mg/mL ofpolysorbate 80, about 50 mg/mL of mannitol, and WFI q.s. to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 56.6 mg/mL of one or morestabilizers, and WFI q.s. to volume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of one or moresurfactants, about 1.6 mg/mL of one or more polymers, about 50 mg/mL ofone or more non-electrolytes, and WFI q.s. to volume.

In yet further embodiments of the invention, the pharmaceuticalcomposition comprises about 100 mg/mL fulvestrant, about 5 mg/mL ofpolysorbate 80, about 1.6 mg/mL of PLASDONE™ C-12 povidone, povidoneK12, or a mixture thereof, about 50 mg/mL of mannitol, and WFI q.s. tovolume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 57.4 mg/mL of one or morestabilizers, and WFI q.s. to volume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of one or moresurfactants, about 2.4 mg/mL of one or more polymers, about 50 mg/mL ofone or more non-electrolytes, and WFI q.s. to volume.

In yet further embodiments of the invention, the pharmaceuticalcomposition comprises about 100 mg/mL fulvestrant, about 5 mg/mL ofpolysorbate 80, about 2.4 mg/mL of PLASDONE™ C-12 povidone, povidoneK12, or a mixture thereof, about 50 mg/mL of mannitol, and WFI q.s. tovolume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,between about 1 mg/mL and 2.4 mg/mL of PVP, sorbitan palmitate,poloxamer 188, poloxamer 124, poloxamer 427, polyethoxylated castor oil,PVA, or a mixture thereof, about 50 mg/mL of mannitol, and WFI q.s. tovolume.

In further embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,about 2.4 mg/mL of PVA, about 50 mg/mL of mannitol, and WFI q.s. tovolume.

In yet further embodiments of the invention, the pharmaceuticalcomposition comprises about 100 mg/mL fulvestrant, about 5 mg/mL ofpolysorbate 80, about 1.0 mg/mL of polyethoxylated castor oil, about 50mg/mL of mannitol, and WFI q.s. to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,about 2.0 mg/mL of poloxamer 188, about 50 mg/mL of mannitol, and WFIq.s. to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,about 1.5 mg/mL of poloxamer 188, about 50 mg/mL of mannitol, and WFIq.s. to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,about 1.5 mg/mL of sorbitan palmitate, about 50 mg/mL of mannitol, andWFI q.s. to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,about 1.5 mg/mL of poloxamer 124, about 50 mg/mL of mannitol, and WFIq.s. to volume.

In certain embodiments of the invention, the pharmaceutical compositioncomprises about 100 mg/mL fulvestrant, about 5 mg/mL of polysorbate 80,about 1.5 mg/mL of poloxamer 407, about 50 mg/mL of mannitol, and WFIq.s. to volume.

Aspects of some exemplary embodiments of pharmaceutical compositionscomprising fulvestrant are shown in Tables 1-20 and 23-27.

In the Figures and specification, references are made to exemplaryformulations. Some exemplary formulations are identified as “F###” whereeach “#” is a numeral, e.g., F001, F002, and so on. The exemplaryformulations sharing an initial identification “F###” share identicalconcentrations of constituent components (mg/mL), but may vary in theirproperties due to different methods of preparation, particle sizedistributions of fulvestrant, or other differences in processing,storage, or handling. Such exemplary formulation sharing an initialidentification scheme “F###” are further identified by extraalphanumeric characters. For example, the exemplary formulations F003a,F003b, and F003k2 have the same concentrations of constituent componentsbut may differ in, e.g., the underlying methods of preparation andresulting particle size distributions. In some instances in the Figures,formulations are identified by only ending non-zero numerals # or ## andsubsequent alphanumeric characters; for example, formulation F003a maybe referred to as “Variant 3a”, formulation F005a2 may be referred to as“Variant 5a2”, and the like. Some exemplary formulations are identifiedand referred to as “Lot”s, with references to the same Lot numberreferring to exemplary formulations having the same concentrations ofconstituent components, but may vary in their properties due todifferent methods of preparation, particle size distributions offulvestrant, or other differences in processing, storage, or handling.

TABLE 1 Target Formulation (mg/mL) Formulation B Formulation EFormulation I Fulvestrant 50 50 50 Polysorbate 80 5 5 5 PVP 12K 0.8 0.80.8 NaCl 9 WFI q.s. to volume q.s. to volume q.s. to volume Assay (% LC)100.0 93.5 94.0 Total Impurities (% a/a) 0.2 0.3 0.2 PSD (via laserdiffraction) as is sonicated as is sonicated as is sonicated Day 0 (μm)LD Dv(10) 7.4 6.0 2.4 1.9 NA NA LD Dv(50) 35.0 32.0 5.2 3.9 LD Dv(90)143 129 11.1 8.7 (μm) day 5 day 1 day 4 LD Dv(10) 7.6 2.3 2.3 1.2 2.50.04 LD Dv(50) 31.9 5.7 5.0 1.8 5.6 0.8 LD Dv(90) 107 19.2 10.9 2.5 12.33.2 (μm) day 14 Day 10 Day 11 LD Dv(10) 5.9 5.1 1.9 1.8 2.3 0.06 LDDv(50) 27.5 24.4 4.0 3.8 4.8 1.3 LD Dv(90) 86.3 76.0 9.1 9.4 9.4 3.7(μm) Day 77 Day 71 Day 12 LD Dv(10) 5.4 4.8 2.1 1.8 2.4 0.2 LD Dv(50)26.3 21.0 4.7 3.8 5.1 3.0 LD Dv(90) 88.7 62.2 12.5 9.7 11.4 6.3 pH 7.4(day 11) 6.9 (day 7) 7.1 (day 4)  pH N/A N/A 6.9 (day 11)

TABLE 2 Target Formulation (mg/mL) Formulation J Formulation KFormulation L Fulvestrant 50 50 100 Polysorbate 80 5 5 5 PVP 12K 0.8 0.80.8 NaCl 9 9 9 Phosphate buffer* 10 mM 10 mM 10 mM WFI q.s. to volumeq.s. to volume q.s. to volume Assay (% LC) 80.9 82.4 94.1 TotalImpurities (% a/a) 0.2 0.2 0.2 PSD (via laser diffraction) as issonicated as is sonicated as is sonicated Day 0 (μm) LD Dv(10) 2.2 1.80.04 0.04 2.4 1.9 LD Dv(50) 5.4 4.2 1.9 1.1 5.0 4.1 LD Dv(90) 11.8 10.34.7 3.6 10.4 8.4 (μm) day 5 day 4 Day 0 LD Dv(10) 2.0 1.7 0.03 0.04 2.41.9 LD Dv(50) 4.7 3.8 1.4 1.1 5.0 4.1 LD Dv(90) 9.7 8.2 3.6 3.0 10.4 8.4(μm) Day 12 Day 11 Day 11 LD Dv(10) 2.1 1.8 1.8 0.05 2.0 2.0 LD Dv(50)5.2 4.2 3.6 2.1 4.0 4.0 LD Dv(90) 14.8 14.5 6.9 4.9 7.6 7.8 (μm) Day 13Day 12 Day 11 LD Dv(10) 2.3 1.9 2.2 0.06 2.5 2.2 LD Dv(50) 5.9 4.6 4.52.3 5.3 5.0 LD Dv(90) 16.5 16.0 11.1 5.6 10.8 10.6 pH 7.0 (day 4)  7.0(day 1)  pH 7.0 (day 11) 7.1 (day 12)

TABLE 3 Target Formulation (mg/mL) Formulation L3F Formulation L6Fulvestrant 50 100 Polysorbate 80 5 5 PVP 12K 0.8 0.8 NaCl 9 9 Phosphatebuffer* 10 mM 10 mM WFI q.s. to volume q.s. to volume Assay (mg/mL) 83.8113.9 Total Impurities (% a/a) 0.7 0.2 PSD (via laser diffraction) as issonicated as is sonicated Day 0 (μm) LD Dv(10) 2.1 2.0 2.2 2.1 LD Dv(50)5.9 5.5 6.9 6.7 LD Dv(90) 14.7 14.2 17.6 17.7 (μm) Day 14 Day 1 LDDv(10) 2.1 2.0 2.1 2.1 LD Dv(50) 5.7 5.5 6.8 6.6 LD Dv(90) 14.4 14.018.0 17.7 pH 7.1 (day 1)

TABLE 4 Target Formulation F003a F003b F004a Fulvestrant 100 100 100Polysorbate 80 5 5 5 Dextrose 50 50 NaCl 9 WFI q.s. to volume q.s. tovolume q.s. to volume Manufacturing Process API size reduction by APIsize reduction by API size reduction by HSM only HSM followed by HPH HSMfollowed by HPH Assay (mg/mL) 95.0 96.3 99.8 Total Impurities (% 0.420.28 0.27 PSD (via laser diffraction) as is sonicated as is sonicated asis sonicated Day 0 LD 1.9 1.9 2.2 1.6 1.9 1.5 (μm) LD 5.3 5.2 6.0 3.95.8 3.5 LD 13.0 12.7 12.1 7.6 12.2 7.7 (μm) Day 13 Day 13 Day 13 LDDv(10) 1.9 1.9 2.1 1.7 1.7 1.5 LD Dv(50) 5.3 5.2 5.5 4.2 4.0 3.3 LDDv(90) 13.4 13.0 11.3 8.2 8.7 6.8 (μm) Day 13 Day 13 Day 13 LD Dv(10)1.8 1.7 2.1 1.7 1.7 1.6 LD Dv(50) 5.1 4.9 5.9 4.3 4.0 3.4 LD Dv(90) 13.013.2 12.1 8.4 8.6 6.3 pH 7.3 (Day 0)  7.5 (Day 0)  pH 7.1 (Day 13) 7.1(Day 13)

TABLE 5 Target Formulation (mg/mL) F003e F003k2 F003k3 Fulvestrant 100100 100 Polysorbate 80 5 5 5 Dextrose 50 50 50 WFI q.s. to voltune q.s.to volume q.s. to volume Manufacturing Process Micronized API MicronizedAPI Micronized API dispersed dispersed by vortex/ dispersed by HSM byHSM followed by HPH sonics or HSM for size reduction Assay (mg/mL) 100.597.8 99.6 Total Impurities (% a/a) 0.34 0.43 0.42 PSD (via laserdiffraction) as is sonicated as is sonicated as is sonicated Day 0 (μm)LD Dv(10) 1.5 1.5 1.5 1.4 2.2 1.4 LD Dv(50) 3.9 3.8 2.9 2.6 7.0 3.4 LDDv(90) 13.0 12.8 6.7 6.3 13.3 7.4 (μm) Day 1 Day 5 Day 1 LD Dv(10) 1.51.5 NA NA NA NA LD Dv(50) 4.0 4.0 LD Dv(90) 12.4 12.5 (μm) Day 13 Day 12Day 8 LD Dv(10) 1.5 1.5 1.6 1.5 1.5 1.3 LD Dv(50) 4.1 4.1 3.2 2.9 2.92.6 LD Dv(90) 14.0 14.3 7.0 6.5 5.7 5.2 (μm) Day 22 Day 12 Day 8 LDDv(10) 1.5 1.5 1.5 1.4 1.4 1.1 LD Dv(50) 3.9 3.9 3.0 2.8 2.8 1.9 LDDv(90) 12.6 12.8 6.7 6.1 6.2 3.5 pH 7.2 (day 1)   7.2 (day 0)  pH 4.5(Day 12) 6.8 (Day 8)

TABLE 6 Target Formulation (mg/mL) F003i F005a2 F005b1 Fulvestrant 100100 100 Polysorbate 80 5 5 5 Dextrose 50 Mannitol 50 50 WFI q.s. tovolume q.s. to volume q.s. to volume Manufacturing Process Reconstitutedlyophilized Reconstituted lyophilized Micronized API suspension,micronized suspension, API sized dispersed by HSM API dispersed by HSMreduction by HSM Assay (mg/mL) 99.2 93.2 100.2 Total Impurities (% a/a)0.46 0.55 0.36 PSD (via laser diffraction) as is sonicated as issonicated as is sonicated Day 0 (μm) LD 4.6 1.7 2.1 2.0 1.5 1.4 LD 54.25.6 6.5 5.6 3.2 2.7 LD 112 16.2 18.4 13.5 7.9 6.6 (μm) Day 9 Day 8 Day13 LD 2.5 1.5 2.1 2.0 LD 39.5 4.3 6.2 5.4 LD Dv(90) 95.1 13.5 16.7 13.2pH 6.5 (Day 3) 7.4 (Day 0) pH 7.2 (Day 9)

TABLE 7 Target Formulation (mg/mL) F005c2 F0017a F0015a Fulvestrant 100100 100 Polysorbate 80 5 15 25 Mannitol 50 50 50 WFI q.s. to volume q.s.to volume q.s. to volume Manufacturing Process Micronized API dispersedMicronized API Micronized API by HSM followed by HPH dispersed by HSMdispersed by HSM for size reduction Assay (mg/mL) 100.2 103.8 TotalImpurities (% a/a) 0.39 PSD (via laser diffraction) as is sonicated asis sonicated as is sonicated Day 0 (μm) LD 1.3 1.1 1.5 1.4 1.5 1.4 LD2.3 1.9 3.0 2.6 2.9 2.6 LD 4.9 3.7 7.2 6.4 6.9 6.4 pH 7.1 (day 0) 7.1(day 0)

TABLE 8 Formulation/Variants mg/mL I J K L M N O, O2 Fulvestrant 50 5050 100 100 100 100 Polysorbate 80 5 5 5 5 5 5 5 Povidone K12 0.8 0.8 0.80.8 0.8 0.8 0.8 Sodium Chloride 9 9 9 9 9 4.5 Dextrose 25 50NaH₂PO₄•2H₂O 0.61 0.61 0.61 Na₂HPO₄ 0.85 0.85 0.85 WFI QS QS QS QS QS QSQS

TABLE 9 Formulation F001 F002 F003 F004 F005 F015 F016 F017 variants(mg/mL) F003a, b, e, F005a, a2, b1, f, g, h, i, j, c, c2, c3, d, g,F015a, F017a, F001e B, E k2, k3, l F004a d1, g4, g5, h3 a1, a3 a1, a3Fulvestrant 100 100 100 100 100 100 100 100 Polysorbate 80 5 5 5 5 5 255 15 Povidone K12 0.8 0.8 Sodium Chloride 9 Dextrose 50 Mannitol 50 5050 50 WFI QS QS QS QS QS QS QS QS

TABLE 10 Formulation mg/mL F003k+ F006 F007 F008 F009 F010 F011 F012F013 F014 Fulvestrant 200 100 100 100 100 100 100 100 100 100Polysorbate 80 5 25 5 5 5 5 5 5 5 5 Dextrose 50 50 50 50 50 50 50 50 5050 Polysorbate 20 15 Poloxamer 188 2 PVP K12 20 PVP K17 5 PEG 3350 60CMC7LF PH 30 CMC7MF PH 20 CMC7HF PH 5 WFI QS QS QS QS QS QS QS QS QS QS

TABLE 11 (mg/mL) F018 F019 F020 F021 F022 F023 F024 F025 F026 F027 F028Fulvestrant 100 100 100 100 100 100 100 100 100 100 100 Polysorbate 80 55 5 5 5 5 5 5 5 5 5 Polysorbate 20 5 15 5 15 5 Poloxamer 188 2 2 2 2Mannitol 50 50 50 50 50 50 50 50 50 50 50 Dextrose NaCl Glycerol PVP K125 10 20 10 PVP K17 5 PEG 3350 60 CMC7LF PH CMC7MF PH CMC7HF PH WFI qs qsqs qs qs qs qs qs qs qs qs

TABLE 12 (mg/mL) F029 F030 F031 F032 F033 F034 F035 F036 Fulvestrant 100100 100 100 100 100 100 100 Polysorbate 80 5 5 5 5 5 5 5 5 Polysorbate20 5 Poloxamer 188 2 Mannitol 50 25 12.5 37.5 50 50 50 50 Dextrose 2537.5 12.5 NaCl Glycerol 30 PVP K12 5 PVP K17 PEG 3350 CMC7LF PH 3 2 1 1CMC7MF PH CMC7HF PH WFI qs qs qs qs qs qs qs qs

TABLE 13 (mg/mL) F037 F038 F039 F040 F041 F042 F043 F044 F045 F046 F047Fulvestrant 100 100 100 100 100 100 100 100 100 100 100 Polysorbate 80 55 5 5 5 5 5 5 5 5 5 Polysorbate 20 5 5 Poloxamer 188 2 2 Mannitol 25 2525 25 12.5 12.5 12.5 12.5 37.5 37.5 37.5 Dextrose 25 25 25 25 37.5 37.537.5 37.5 12.5 12.5 12.5 NaCl Glycerol PVP K12 5 5 PVP K17 PEG 3350CMC7LF PH 3 2 1 1 3 2 1 1 3 2 1 CMC7MF PH CMC7HF PH WFI qs qs qs qs qsqs qs qs qs qs qs

TABLE 14 (mg/mL) F048 F049 F050 F051 F052 F053 F054 F055 Fulvestrant*100 100 100 100 100 100 100 100 Polysorbate 80 5 5 5 5 5 5 5 5Polysorbate 20 5 5 Poloxamer 188 2 2 Mannitol 37.5 25 25 25 25 25 25 25Dextrose 12.5 25 25 25 25 25 NaCl 4.9 9 4.9 4.9 4.9 4.9 4.9 Glycerol PVPK12 5 5 PVP K17 PEG 3350 CMC7LF PH 1 3 2 1 1 CMC7MF PH CMC7HF PH WFI qsqs qs qs qs qs qs qs

TABLE 15 (mg/mL) F056 F057 F058 F059 F060 F061 F062 Fulvestrant 100 100100 100 100 100 100 Polysorbate 80 Polysorbate 20 5 10 15 5 5 10 10Poloxamer 188 Mannitol 50 50 50 50 50 50 50 Dextrose NaCl Glycerol PVPK12 PVP K17 PEG 3350 10 30 10 30 PEG 4000 CMC7LF PH CMC7MF PH CMC7HF PHWFI qs qs qs qs qs qs qs

TABLE 16 (mg/mL) F063 F064 F065 F066 F067 F068 F069 F070 Fulvestrant 100100 100 100 100 100 100 100 Polysorbate 80 Polysorbate 20 15 15 5 5 1010 15 15 Poloxamer 188 Mannitol 50 50 50 50 50 50 50 50 Dextrose NaClGlycerol PVP K12 PVP K17 PEG 3350 10 30 PEG 4000 3 7.5 3 7.5 3 7.5CMC7LF PH CMC7MF PH CMC7HF PH WFI qs qs qs qs qs qs qs qs

TABLE 17 Formulations/Variants Component Q R S T U V W X Fulvestrant(mg/mL) 100  100  100  100  100  100  100  100  Polysorbate 80 25 5 — —5  5 —  5 (mg/mL) Polysorbate 20 — — 5 — — — — — (mg/mL) Poloxamer 188 —— — 5 — — — — (mg/mL) Lecithin (mg/mL) — — — — — — 5 — PVP K12 (mg/mL)  0.8 5   0.8   0.8 — —   0.8   0.8 PVP K17 (mg/mL) — — — —   0.8 — — —PEG 3350 (mg/mL) — — — — — 50 — — Dextrose (mg/mL) 50 — — SodiumChloride — 9 13  (mg/mL) NaOH QS to QS to QS to QS to QS to QS to QS topH QS to pH 7.0 pH 7.0 pH 7.0 pH 7.0 pH 7.0 pH 7.0 7.0 pH 7.0 HCl QS toQS to QS to QS to QS to QS to QS to pH QS to pH 7.0 pH 7.0 pH 7.0 pH 7.0pH 7.0 pH 7.0 7.0 pH 7.0 WFI QS to QS to QS to QS to QS to QS to QS QSto volume volume volume volume volume volume to volume volume

TABLE 18 Formulations/Variants Component 1 2 3 4 5 6 7 8 Fulvestrant100  100  100  100  100  100  100  100  (mg/mL) Polysorbate 80 — 5 — — 55 — 5 (mg/mL) Polysorbate 20 — — 5 — — — — — (mg/mL) Poloxamer 188 — — —5 — — — — (mg/mL) Human Serum 5 Albumin (mg/mL) Lecithin (mg/mL) — — — —— — 5 — PVP K12   0.8 5   0.8   0.8 — —   0.8   0.8 (mg/mL) PVP K17 — —— —   0.8 — — — (mg/mL) PEG 3350 — — — — — 50  — — (mg/mL) Dextrose 5050  — (mg/mL) Mannitol (mg/mL) — — 50  Citric buffer QS to QS to QS toQS to QS to QS to QS to pH QS to pH 7.0 pH 7.0 pH 7.0 pH 7.0 pH 7.0 pH7.0 7.0 pH 7.0 WFI QS to QS to QS to QS to QS to QS to QS QS to volumevolume volume volume volume volume to volume volume

TABLE 19 Formulation (mg/mL) F005g4 Lot Lot Lot Lot Lot Lot Lot F005g5Lot 15 26 27 28 42 43 X1 X2 Fulvestrant 100  100  100  100  100  100 100  100  100  Polysorbate 80 5 5  5 5 5  5  5  5  5 PVPC12 — —   1.6  1.6 — — — — Span 40 — — — —   1.5 — — — Pluronic F-68   1.5 PluronicL44   1.5 Pluronic F127   1.5 Mannitol (before 50  50  — 50  — 50 50 5050 homogenization) Mannitol (after — 50 — 50  homogenization)

TABLE 20 Formulation (mg/mL) Lot Lot Lot Lot 45 46 47 48 Fulvestrant 100100 100 100 Polysorbate 80 5 5 5 5 PVPC12 2.4 — Span 40 — — PluronicF-68 2 Cremophor EL 1 PVA 2.4 Mannitol 50 50 50 50 (beforehomogenization)

TABLE 21 Sample Density Name (g/ml) F003h 1.032 F003f 1.032 F003e 1.032F003k2 1.030

TABLE 22 Sample Viscosity Name Formulation (cps) Placebo 5 mg/mL PS80 +50 mg/mL 1.1 Dextrose F003h [Described elsewhere] 1.8 F003f [Describedelsewhere] 1.9 F003k [Described elsewhere] 2.0 F003e [Describedelsewhere] 1.5

B. Fulvestrant Particles

Particular embodiments of the disclosure comprise solid fulvestrantparticles, for example a fulvestrant suspension comprising solidfulvestrant particles. In certain embodiments of the invention, at leastabout 90% of the total fulvestrant in the formulation is present assolid particles. In further embodiments of the invention, at least about80% of the total fulvestrant in the formulation is present as solidparticles.

In certain embodiments of the invention, solid fulvestrant particles areparticles consisting of crystalline and/or amorphous fulvestrant. Inother embodiments of the invention, fulvestrant particles comprisecrystalline and/or amorphous fulvestrant as well as other excipients. Instill other embodiments, fulvestrant particles comprise crystallineand/or amorphous fulvestrant coated or surface modified by a surfacemodifier adsorbed on the surface of the particle. The surface modifiercan be a stabilizer such as, but not limited to surfactants, polymers,electrolytes, and non-electrolytes, and mixtures thereof.

Other embodiments of the present invention may further comprisefulvestrant in forms other than a solid particle, such as, but notlimited to, solubilized fulvestrant as a free molecule or associatedwith a suspension such as micelles, microemulsions, emulsion, liposome,and combinations thereof, or complexed with other formulationconstituents in a vehicle. In further embodiments of the invention, suchother forms of fulvestrant are in equilibrium with the fulvestrant solidparticles.

In particular embodiments of the invention, the fulvestrant particlescomprise about 90-99.9% by weight of fulvestrant and 0.1-10% by weightof a surface modifier adsorbed on the surface of said particle. Inparticular embodiments of the invention, the surface modifier is astabilizer such as, but not limited to surfactants, polymers,electrolytes, and non-electrolytes, and mixtures thereof. In certainembodiments of the invention, fulvestrant particles comprise at leastabout 90% fulvestrant. In other embodiments of the invention fulvestrantparticles comprise at least about 92%, 95%, 97%, 98%, 99%, 99.5%, or99.9% fulvestrant.

In further embodiments of the invention, one or more solvents, such aswater, present in the pharmaceutical composition can be removedpartially or completely by appropriate techniques known to the art, suchas lyophilization or spray drying, to form a dried pharmaceuticalcomposition for reconstitution. In certain embodiments of the invention,the dried pharmaceutical composition can comprise up to about 1%, about2%, about 5%, or about 10% of the one or more solvents. The driedpharmaceutical composition can be reconstituted with appropriate diluentknown to the art, such as, but not limited to water for injection (WFI),normal saline (NS), and 5% dextrose in water (D5W) prior toadministration. In further embodiments of the invention, the diluent canfurther comprise an organic solvent or one or more of the excipientsdescribed herein. Dried pharmaceutical compositions formed bylyophilization may be in the form of a lyophilized cake.

Fulvestrant Particle Sizes

In certain embodiments of the invention, the fulvestrant particles havea laser diffraction diameter greater than or equal to about 1 micron. Inyet further embodiments of the invention, at least a portion of thefulvestrant particles have a laser diffraction diameter less than about1 micron. In other embodiments of the invention the fulvestrantparticles have a laser diffraction diameter greater than or equal toabout 2 microns. In still other embodiments of the invention, at least aportion of the fulvestrant particles have a laser diffraction diameterless than about 2 microns.

In certain embodiments of the invention, the fulvestrant particles havea laser diffraction diameter greater than or equal to about 0.5 microns.In other embodiments of the invention, at least a portion of thefulvestrant particles have a laser diffraction diameter less than about0.5 microns. In other embodiments of the invention, the fulvestrantparticles have a laser diffraction diameter greater than or equal toabout 1 micron. In other embodiments of the invention, at least aportion of the fulvestrant particles have a laser diffraction diameterless than about 1 microns. In still other embodiments of the invention,the fulvestrant particles have a laser diffraction diameter greater thanor equal to about 1.5 microns. In other embodiments of the invention, atleast a portion of the fulvestrant particles have a laser diffractiondiameter less than about 1.5 microns. In yet other embodiments of theinvention, the fulvestrant particles have a laser diffraction diametergreater than or equal to about 2 microns. In other embodiments of theinvention, at least a portion of the fulvestrant particles have a laserdiffraction diameter less than about 2 microns.

In further embodiments of the invention, about 98% of fulvestrantparticles have a laser diffraction diameter greater than or equal toabout 0.5 microns. In other embodiments of the invention, about 98% offulvestrant particles have a laser diffraction diameter greater than orequal to about 1 micron. In still other embodiments of the invention,about 98% of fulvestrant particles have a laser diffraction diametergreater than or equal to about 1.5 microns. In yet other embodiments ofthe invention, about 98% of fulvestrant particles have a laserdiffraction diameter greater than or equal to about 2 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(90) between about 4 microns and about 120 microns, betweenabout 4 microns and about 100 microns, between about 4 microns and about75 microns, between about 4 microns and about 60 microns, between about4 microns and about 50 microns, between about 4 microns and about 40microns, between about 4 microns and about 30 microns, between about 4microns and about 20 microns, between about 4 microns and about 15microns, between about 4 microns and about 10 microns, between about 20microns and about 60 microns, between about 20 microns and about 45microns, between about 20 microns and about 30 microns, between about 30microns and about 50 microns, or between about 4 microns and about 9microns. In other embodiments of the invention, the fulvestrantparticles have a LD Dv(90) equal to about 4 microns, about 5 microns,about 6 microns, about 7 microns, about 8 microns, about 9 microns,about 10 microns, about 11 microns, about 12 microns, about 13 microns,about 14 microns, about 15 microns, about 16 microns, about 17 microns,about 18 microns, about 19 microns, about 20 microns, about 25 microns,about 30 microns, about 35 microns, about 40 microns, about 45 microns,about 50 microns, about 55 microns, about 60 microns, about 65 microns,about 70 microns, about 75 microns, about 80 microns, about 85 microns,about 90 microns, about 95 microns, about 100 microns, about 105microns, about 110 microns, about 115 microns, or about 120 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(90) less than or equal to about 120 microns. In certainembodiments of the invention, the fulvestrant particles have an LDDv(90) less than or equal to about 100 microns. In certain embodimentsof the invention, the fulvestrant particles have an LD Dv(90) less thanor equal to about 80 microns. In certain embodiments of the invention,the fulvestrant particles have an LD Dv(90) less than or equal to about60 microns. In certain embodiments of the invention, the fulvestrantparticles have an LD Dv(90) less than or equal to about 50 microns. Incertain embodiments of the invention, the fulvestrant particles have anLD Dv(90) less than or equal to about 40 microns. In certain embodimentsof the invention, the fulvestrant particles have an LD Dv(90) less thanor equal to about 30 microns. In further embodiments of the invention,the particles have an LD Dv(90) less than or equal to about 25 microns.In further embodiments of the invention, the particles have an LD Dv(90)less than or equal to about 18 microns. In further embodiments of theinvention, the particles have an LD Dv(90) less than or equal to about16 microns. In further embodiments of the invention, the particles havean LD Dv(90) less than or equal to about 14 microns. In still furtherembodiments of the invention, the particles have an LD Dv(90) less thanor equal to about 11 microns. In yet further embodiments of theinvention, the particles have an LD Dv(90) less than or equal to about 9microns. In yet further embodiments of the invention, the particles havean LD Dv(90) less than or equal to about 7 microns. In yet furtherembodiments of the invention, the particles have an LD Dv(90) less thanor equal to about 5 microns. In particular embodiments of the invention,particles have an LD Dv(90) between about 9-14 microns. In otherembodiments of the invention, the particles have an LD Dv(90) betweenabout 12-14 microns. In yet other embodiments of the invention, theparticles have an LD Dv(90) between about 9-11 microns. In yet otherembodiments of the invention, the particles have an LD Dv(90) betweenabout 7-9 microns. In yet other embodiments of the invention, theparticles have an LD Dv(90) between about 6-8 microns. In yet otherembodiments of the invention, the particles have an LD Dv(90) betweenabout 6-7 microns. In yet other embodiments of the invention, theparticles have an LD Dv(90) between about 3-6 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(50) between about 2 microns and about 35 microns, between about2 microns and about 25 microns, between about 2 microns and about 20microns, between about 2 microns and about 15 microns, between about 2microns and about 10 microns, between about 2 microns and about 8microns, between about 2 microns and about 7 microns, between about 2microns and about 6 microns, between about 2 microns and about 5microns, between about 2 microns and about 4 microns, between about 5microns and about 10 microns, between about 5 microns and about 15microns, between about 7 microns and about 10 microns, between about 8microns and about 10 microns, or between about 9 microns and about 16microns. In other embodiments of the invention, the fulvestrantparticles have a LD Dv(50) equal to about 2 microns, 3 microns, 4microns, about 5 microns, about 6 microns, about 7 microns, about 8microns, about 9 microns, about 10 microns, about 11 microns, about 12microns, about 13 microns, about 14 microns, about 15 microns, about 16microns, about 17 microns, about 18 microns, about 19 microns, about 20microns, about 25 microns, about 30 microns, or about 35 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(50) less than or equal to about 9 microns. In other embodimentsof the invention, the particles have an LD Dv(50) less than or equal toabout 7 microns. In other embodiments of the invention, the particleshave an LD Dv(50) less than or equal to about 6 microns. In yet otherembodiments of the invention, the particles have an LD Dv(50) less thanor equal to about 5 microns. In particular embodiments of the invention,the particles have an LD Dv(50) less than or equal to about 4 microns.In further embodiments of the invention, the particles have an LD Dv(50)less than or equal to about 3 microns. In further embodiments of theinvention, the particles have an LD Dv(50) between about 4-6 microns. Infurther embodiments of the invention, the particles have an LD Dv(50)between about 3-5 microns. In yet further embodiments of the invention,the particles have an LD Dv(50) between about 3-4 microns. In yetfurther embodiments of the invention, the particles have an LD Dv(50)between about 2-3 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(10) no more than about 3 microns, about 2 microns, or about 1microns. In further embodiments of the invention, the particles have anLD Dv(10) between about 1 micron and about 3 microns. In still furtherembodiments of the invention, the particles have an LD Dv(10) greaterthan or equal to about 2 microns. In yet further embodiments of theinvention, the particles have an LD Dv(10) between about 1.5 microns toabout 2.5 microns. In yet further embodiments of the invention, theparticles have an LD Dv(10) between about 1 micron to about 2 microns.In yet further embodiments of the invention, the particles have an LDDv(10) between about 1.0 micron to about 1.5 microns. In even furtherembodiments of the invention, the particles have an LD Dv(10) of about 2microns. In even further embodiments of the invention, the particleshave an LD Dv(10) of about 1.5 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(90) less than or equal to about 25 microns and an LD Dv(50)less than or equal to about 9 microns. In particular embodiments of theinvention, the particles have an LD Dv(90) less than or equal to about16 microns and an LD Dv(50) less than or equal to about 6 microns. Inother embodiments of the invention, the particles have an LD Dv(90) lessthan or equal to about 11 microns and an LD Dv(50) less than or equal toabout 5 microns. In yet other embodiments of the invention, theparticles have an LD Dv(90) less than or equal to about 9 microns and anLD Dv(50) less than or equal to about 4 microns. In yet otherembodiments of the invention, the particles have an LD Dv(90) less thanor equal to about 8 microns and an LD Dv(50) less than or equal to about4 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(90) between about 9-14 microns and an LD Dv(50) between about4-6 microns. In still other embodiments of the invention, the particleshave an LD Dv(90) between about 9-11 microns and an LD Dv(50) betweenabout 4-6 microns. In particular embodiments of the invention, theparticles have an LD Dv(90) between about 12-14 microns and an LD Dv(50)between about 4-6 microns. In further embodiments of the invention, theparticles have an LD Dv(90) between about 6-8 microns and an LD Dv(50)between about 2-4 microns. In further embodiments of the invention thefulvestrant particles have a laser diffraction diameter greater than orequal to about 1 micron. In yet further embodiments of the invention, atleast a portion of the fulvestrant particles have a laser diffractiondiameter less than about 1 micron. In other embodiments of the inventionthe fulvestrant particles have a laser diffraction diameter greater thanor equal to about 2 microns. In still other embodiments of theinvention, at least a portion of the fulvestrant particles have a laserdiffraction diameter less than about 2 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(90) between about 9-14 microns, an LD Dv(50) between about 4-6microns, and an LD Dv(10) between about 2-3 microns. In otherembodiments of the invention, the particles have an LD Dv(90) betweenabout 9-11 microns, an LD Dv(50) between about 4-6 microns, and an LDDv(10) between about 2-3 microns. In yet other embodiments of theinvention, the particles have an LD Dv(90) between about 12-14 microns,an LD Dv(50) between about 4-6 microns, and an LD Dv(10) between about2-3 microns. In yet other embodiments of the invention, the particleshave an LD Dv(90) between about 6-9 microns, an LD Dv(50) between about2-4 microns, and an LD Dv(10) between about 1-2 microns. In furtherembodiments of the invention the fulvestrant particles have a laserdiffraction diameter greater than or equal to about 1 micron. In yetfurther embodiments of the invention, at least a portion of thefulvestrant particles have a laser diffraction diameter less than about1 micron. In other embodiments of the invention the fulvestrantparticles have a laser diffraction diameter greater than or equal toabout 2 microns. In still other embodiments of the invention, at least aportion of the fulvestrant particles have a laser diffraction diameterless than about 2 microns.

In certain embodiments of the invention, the fulvestrant particles havean LD Dv(90) between about 9-14 microns, an LD Dv(50) between about 4-6microns, and an LD Dv(10) between about 2-3 microns, and the fulvestrantparticles have a laser diffraction diameter greater than or equal toabout 1 micron. In other embodiments of the invention, the particleshave an LD Dv(90) between about 9-14 microns, an LD Dv(50) between about4-6 microns, and an LD Dv(10) between about 2-3 microns, and at least aportion of the fulvestrant particles have a laser diffraction diameterless than about 1 micron. In yet other embodiments of the invention, thefulvestrant particles have an LD Dv(90) between about 30 microns andabout 110 microns, an LD Dv(50) between about 5 microns and about 30microns, and an LD Dv(10) between about 1.5 microns and about 3 microns.In other embodiments of the invention, the particles have an LD Dv(90)between about 9-14 microns, an LD Dv(50) between about 4-6 microns, andan LD Dv(10) between about 2-3 microns, and the fulvestrant particleshave a laser diffraction diameter greater than or equal to about 2microns. In still other embodiments of the invention, the particles havean LD Dv(90) between about 9-14 microns, an LD Dv(50) between about 4-6microns, and an LD Dv(10) between about 2-3 microns, and at least aportion of the fulvestrant particles have a laser diffraction diameterless than about 2 microns. In yet other embodiments of the invention,the particles have an LD Dv(90) between about 6-9 microns, an LD Dv(50)between about 2-4 microns, an LD Dv(10) between about 1-2 microns, andthe fulvestrant particles have a laser diffraction diameter greater thanor equal to about 0.5 microns. In yet other embodiments of theinvention, the particles have an LD Dv(90) between about 6-9 microns, anLD Dv(50) between about 2-4 microns, an LD Dv(10) between about 1-2microns, and at least a portion of the fulvestrant particles have alaser diffraction diameter less than about 0.5 microns. In furtherembodiments of the invention the fulvestrant particles have a laserdiffraction diameter greater than or equal to about 1 micron. In yetfurther embodiments of the invention, at least a portion of thefulvestrant particles have a laser diffraction diameter less than about1 micron. In other embodiments of the invention the fulvestrantparticles have a laser diffraction diameter greater than or equal toabout 2 microns. In still other embodiments of the invention, at least aportion of the fulvestrant particles have a laser diffraction diameterless than about 2 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dv(10) between about 1 microns and about 25 microns, between about2 microns and about 25 microns, between about 3 microns and about 7microns, between about 4 microns and about 15 microns, between about 4microns and about 10 microns, between about 4 microns and about 8microns, between about 6 microns and about 8 microns, between about 6microns and about 7 microns, or between about 1 microns and about 10microns. In other embodiments of the invention, the fulvestrantparticles have a CE Dv(10) equal to about 1 micron, about 2 microns,about 3 microns, about 4 microns, about 5 microns, about 6 microns,about 7 microns, about 8 microns, about 9 microns, about 10 microns,about 11 microns, about 12 microns, about 13 microns, about 14 microns,about 15 microns, about 16 microns, about 17 microns, about 18 microns,about 19 microns, about 20 microns, about 21 microns, about 22 microns,about 23 microns, about 24 microns, or about 25 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dv(50) between about 5 microns and about 60 microns, between about5 microns and about 50 microns, between about 9 microns and about 20microns, between about 9 microns and about 15 microns, between about 10microns and about 50 microns, between about 10 microns and about 40microns, between about 10 microns and about 30 microns, between about 10microns and about 20 microns, between about 15 microns and about 30microns, between about 15 microns and about 25 microns, between about 15microns and about 20 microns, or between about 10 microns and about 15microns. In other embodiments of the invention, the fulvestrantparticles have a CE Dv(50) equal to about 5 micron, about 6 microns,about 7 microns, about 8 microns, about 9 microns, about 10 microns,about 11 microns, about 12 microns, about 13 microns, about 14 microns,about 15 microns, about 16 microns, about 17 microns, about 18 microns,about 19 microns, about 20 microns, about 21 microns, about 22 microns,about 23 microns, about 24 microns, about 25 microns, about 30 microns,about 35 microns, about 40 microns, about 45 microns, about 50 microns,about 55 microns, or about 60 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dv(90) between about 10 microns and about 200 microns, betweenabout 25 microns and about 150 microns, between about 25 microns andabout 125 microns, between about 25 microns and about 100 microns,between about 25 microns and about 75 microns, between about 25 micronsand about 50 microns, between about 25 microns and about 40 microns,between about 25 microns and about 35 microns, between about 35 micronsand about 90 microns, between about 35 microns and about 75 microns,between about 35 microns and about 50 microns, between about 35 micronsand about 45 microns, between about 50 microns and about 100 microns,between about 50 microns and about 75 microns, or between about 20microns and about 40 microns. In other embodiments of the invention, thefulvestrant particles have a CE Dv(90) equal to about 10 microns, about15 microns, about 20 microns, about 25 microns, about 30 microns, about35 microns, about 40 microns, about 45 microns, about 50 microns, about55 microns, about 60 microns, about 65 microns, about 70 microns, about75 microns, about 80 microns, about 85 microns, about 90 microns, about95 microns, about 100 microns, about 105 microns, about 110 microns,about 115 microns, about 120 microns, about 125 microns, about 130microns, about 135 microns, about 140 microns, about 145 microns, about150 microns, about 155 microns, about 160 microns, about 165 microns,about 170 microns, about 175 microns, or about 200 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dv(90) between about 35 microns and about 90 microns, a CE Dv(50)between about 10 microns and about 35 microns, and a CE Dv(10) betweenabout 4 microns and about 10 microns. In other embodiments of theinvention, the particles have a CE Dv(90) between about 25 microns andabout 60 microns, a CE Dv(50) between about 10 microns and about 25microns, and a CE Dv(10) between about 4 microns and about 8 microns. Inother embodiments of the invention, the particles have a CE Dv(90)between about 20 microns and about 35 microns, a CE Dv(50) between about10 microns and about 20 microns, and a CE Dv(10) between about 4 micronsand about 8 microns. In still other embodiments of the invention, theparticles have a CE Dv(90) between about 30 microns and about 100microns, a CE Dv(50) between about 10 microns and about 50 microns, anda CE Dv(10) between about 4 microns and about 10 microns. In yet otherembodiments of the invention, the particles have a CE Dv(90) betweenabout 50 microns and about 100 microns, a CE Dv(50) between about 20microns and about 50 microns, a CE Dv(10) between about 6 microns andabout 8 microns. In yet other embodiments of the invention, theparticles have a CE Dv(90) between about 50 microns and about 75microns, a CE Dv(50) between about 30 microns and about 40 microns, a CEDv(10) between about 8 microns and about 10 microns. In yet otherembodiments of the invention, the particles have a CE Dv(90) betweenabout 20 microns and about 60 microns, a CE Dv(50) between about 9microns and about 20 microns, and a CE Dv(10) between about 3 micronsand about 7 microns. In still further embodiments of the invention, theparticles have a CE Dv(90) between about 20 microns and about 50microns, a CE Dv(50) between about 9 microns and about 20 microns, and aCE Dv(10) between about 3 microns and about 7 microns. In otherembodiments of the invention, the particles have a CE Dv(90) betweenabout 20 microns and about 45 microns, a CE Dv(50) between about 9microns and about 20 microns, and a CE Dv(10) between about 3 micronsand about 7 microns. In yet further embodiments of the invention, theparticles have a CE Dv(90) between about 20 microns and about 40microns, a CE Dv(50) between about 9 microns and about 15 microns, and aCE Dv(10) between about 3 microns and about 7 microns. In furtherembodiments of the invention, the particles have a CE Dv(90) betweenabout 20 microns and about 35 microns, a CE Dv(50) between about 9microns and about 15 microns, and a CE Dv(10) between about 3 micronsand about 7 microns. In still other embodiments of the invention, theparticles have a CE Dv(90) between about 20 microns and about 45microns, a CE Dv(50) between about 9 microns and about 15 microns, and aCE Dv(10) between about 3 microns and about 7 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dn(90) between about 4 microns and about 20 microns, between about6 microns and about 15 microns, between about 6 microns and about 12microns, between about 8 microns and about 12 microns, between about 8microns and about 11 microns, between about 4 microns and about 10microns, between about 4 microns and about 8 microns, between about 4microns and about 7 microns, or between about 4 microns and about 6microns. In other embodiments of the invention, the fulvestrantparticles have a CE Dn(90) equal to about 4 microns, about 5 microns,about 6 microns, about 7 microns, about 8 microns, about 9 microns,about 10 microns, about 11 microns, about 12 microns, about 13 microns,about 14 microns, about 15 microns, about 16 microns, about 17 microns,about 18 microns, about 19 microns, or about 20 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dn(50) between about 2.0 microns and about 10.0 microns, betweenabout 2.0 microns and about 8.0 microns, between about 2.0 microns andabout 6.0 microns, between about 2.0 microns and about 5.0 microns,between about 3.0 microns and about 5.0 microns, between about 3.5microns and about 4.5 microns, between about 2.0 microns and about 4.0microns, between about 2.5 microns and about 4.5 microns, or betweenabout 2.5 microns and about 3.5 microns. In other embodiments of theinvention, the fulvestrant particles have a CE Dn(50) equal to about 2.0microns, about 2.5 microns, about 3.0 microns, about 3.5 microns, about4.0 microns, about 4.5 microns, about 5.0 microns, about 5.5 microns,about 6.0 microns, about 6.5 microns, about 7.0 microns, about 7.5microns, about 8.0 microns, about 8.5 microns, about 9.0 microns, about9.5 microns, or about 10.0 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dn(10) between about 0.5 microns and about 2.0 microns, betweenabout 0.5 microns and about 1.5 microns, between about 1.0 microns andabout 1.5 microns, between about 0.8 microns and about 1.2 microns,between about 0.9 microns and about 1.1 microns, or between about 0.5microns and about 1.0 microns. In other embodiments of the invention,the fulvestrant particles have a CE Dn(10) equal to about 0.5, about0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2,about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about1.9, or about 2.0 microns.

In certain embodiments of the invention, the fulvestrant particles havea CE Dn(90) between about 4 microns and about 20 microns, a CE Dn(50)between about 2.0 microns and about 10.0 microns, and a CE Dn(10)between about 0.5 microns and about 2.0 microns. In other embodiments ofthe invention, the fulvestrant particles have a CE Dn(90) between about6 microns and about 12 microns, a CE Dn(50) between about 2.0 micronsand about 6.0 microns, and a CE Dn(10) between about 0.5 microns andabout 1.5 microns. In further embodiments of the invention, thefulvestrant particles have a CE Dn(90) between about 8 microns and about1 microns, a CE Dn(50) between about 3.0 microns and about 5.0 microns,and a CE Dn(10) between about 0.8 microns and about 1.2 microns.

C. Preparation Methods

In certain embodiments of the invention, formulations of the inventioncan be prepared from commercially available fulvestrant having differentparticle size distributions, such as, for example, recrystallized,micronized fulvestrant, or a combination thereof. In further embodimentsof the invention, the formulations are prepared with sterilized,commercially available fulvestrant. In particular embodiments,commercially available fulvestrant is used in the formulations of thepresent invention without further processing for size reduction.

In other embodiments of the invention, fulvestrant particles suitablefor use in formulations of the invention can be prepared fromcommercially available fulvestrant by any suitable methods known in theart. Suitable methods include, but are not limited to, size-reductiontechniques such as milling, grinding, crushing, compression, attrition,low shear mixing, high shear mixing, high pressure homogenization,lyophilization, precipitation, or combinations thereof.

Desired particle size distributions for fulvestrant particles can beachieved by processing steps at one or more stages of formulationpreparation. In some embodiments, the desired particle size distributioncan be formed by processing fulvestrant material prior to suspension inmedia, by techniques described more fully elsewhere herein. In otherembodiments, the desired particle size distribution can be formed byprocessing after suspension in media, by techniques described more fullyelsewhere herein, including but not limited to high shear mixing andhigh pressure homogenization. In still other embodiments, the desiredparticle size distribution can be formed by a combination of theprocessing prior to and after suspension in media.

Suitable milling techniques include, but are not limited to, drymilling, wet milling, and cryogenic milling. Suitable milling machinesinclude ball mills, pebble mills, rod mills, roller mills, colloidmills, impact mills, and jet mills. In certain embodiments of theinvention, the particles can be reduced in size in the presence of oneor more excipients or stabilizers, such as but not limited to asurfactants, polymers, electrolytes, and non-electrolytes, and mixturesthereof. Alternatively, the particles can be contacted with one or moreexcipients or stabilizers after they are reduced in size.

In certain embodiments of the invention, the formulations can beprepared from an un-milled commercially available fulvestrant byreducing the fulvestrant particle size with high shear mixing. In yetfurther embodiments of the invention, the formulations can be preparedfrom an un-milled, commercially available fulvestrant by reducing thefulvestrant particle size with high shear mixing followed by highpressure homogenization.

In certain embodiments of the invention, the formulations can beprepared from commercially available micronized fulvestrant by reducingthe micronized fulvestrant particle size with high shear mixing (“HSM”).In yet further embodiments of the invention, the formulations can beprepared from an un-milled commercially available fulvestrant byreducing the fulvestrant particle size with high shear mixing followedby high pressure homogenization (“HPH”).

In some embodiments of the invention, the formulations can be preparedusing high pressure homogenization. In further embodiments of theinvention, the high pressure homogenization process reduces particlesize by subjecting the particle population to one or more of cavitation,shear, and impact within a homogenization chamber under operatingpressures from about 5,000 psi to about 45,000 psi, for example, about5,000, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000 or about45,000 psi. In yet further embodiments of the invention, the highpressure homogenization process is performed at about 40,000 psi. Insome embodiments of the invention, the high pressure homogenizationprocess is performed at operating pressures from about 15,000 psi toabout 20,000 psi. In further embodiments, the formulations can beprepared by passing the formulation suspension through a homogenizationchamber under operating pressures for one or more passes, for example,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, or 50 passes.

In the Figures and specification, references are made to exemplaryformulations and processes for preparing exemplary formulations. Someexemplary preparation processes are identified with alphanumericreference identifiers, such as “Process A1,” “Process A2,” and so on.Some exemplary formulations can share identical concentrations ofconstituent components (mg/mL), but may vary in their properties due tothe different preparation processes, storage, or handling, which canresult in different particle size distributions due to more or less sizereduction, more or less aggregation or agglomeration, or both duringprocessing, storage, or handling.

Methods of Forming Aqueous Fulvestrant Suspensions

In some embodiments of the invention, methods of forming an aqueousfulvestrant suspension comprise mixing an aqueous medium and at leastone stabilizer to form a suspension vehicle, adding an amount offulvestrant to the suspension vehicle, and dispersing the fulvestrant inthe suspension vehicle to form the aqueous fulvestrant suspension. Infurther embodiments, these methods can further comprise homogenizing theaqueous fulvestrant suspension. In yet further embodiments, the methodswith or without the homogenizing step can further comprise concentratingthe fulvestrant suspension by phase separating the suspension andremoving a portion of the supernatant. In particular furtherembodiments, after the concentrating step the methods can furthercomprise adding one or more electrolytes, non-electrolytes, bufferingagents, or cross-linked polymers to the homogenized aqueous fulvestrantsuspension and mixing the one or more electrolytes, non-electrolytes,buffering agents, or cross-linked polymers into the suspension. In someembodiments of the invention, the methods comprise a dispersing stepperformed using high shear mixing, a homogenizing step performed usinghigh pressure homogenization, or both a dispersing step performed usinghigh shear mixing and a homogenizing step performed using high pressurehomogenization.

In further embodiments of the invention that include one or morestabilizers, the one or more stabilizers may be incorporated into theformulations at one or more stages of the methods of forming theformulations. In some embodiments, at least a portion or all of thestabilizers of a formulation are added to an aqueous medium along withan amount of fulvestrant prior to some or all of any mixing,homogenization, or supernatant-removal steps. In still otherembodiments, at least a portion or all of the one or more stabilizers ofa formulation are added to the fulvestrant suspensions after some or allof any mixing, homogenization, or supernatant-removal steps have beencompleted. In further embodiments, at least a portion or all of thesurfactant and polymer stabilizers of the formulations are combined withthe aqueous medium and fulvestrant prior to some or all of any mixing,homogenization, or supernatant-removal steps and at least a portion orall of the electrolyte, non-electrolyte, buffering agents, andcross-linked polymers of the formulations are added to the suspensionafter some or all of any mixing, homogenization, or supernatant-removalsteps.

The fulvestrant particles described herein can be prepared in a methodcomprising the steps of dispersing fulvestrant particles in a liquidsuspension medium and applying mechanical means in the presence ofgrinding media to reduce the particle size of fulvestrant to the desiredsize.

In further embodiments of the invention, a solvent, such as water,present in a formulation can be removed by appropriate techniques knownto the art, such as lyophilization or spray drying, to form a driedformulation suitable for later reconstitution. Lyophilization can beused to produce a lyophilized (lyo) cake. The dried formulation can bereconstituted back into a liquid suspension using an appropriatediluent. Different volumes of diluent can be used to producereconstituted suspensions with different fulvestrant concentrations asneeded. The diluent can be aqueous in general but can further comprisean organic solvent and/or any excipient as described elsewhere herein.

In some embodiments of the invention, at least a portion of theformulation components other than fulvestrant can be omitted from thesuspension and incorporated as part of the diluent and introduced intothe suspension upon reconstitution by the diluent to arrive at the finalformulation. In further embodiments, suspensions can be prepared withhigher or lower concentrations of constituent components than desired informulations for administration, formed into dried formulations andplaced into vials in appropriate amounts of dried formulation to achievetarget dose amounts of fulvestrant per vial for later reconstitution ofdiluent to form the desired formulation for administration.

Some exemplary methods of preparation of dried pharmaceuticalcompositions are depicted schematically in FIG. 15.

In some embodiments, the pharmaceutical compositions and driedpharmaceutical compositions can be prepared using aseptic process orterminally sterilized by a compatible sterilization technique, such as,but not limited to, gamma irradiation. When a polymer is used as anexcipient in the pharmaceutical composition, said polymer such asmicrocrystalline cellulose (CMC) or its salts including sodium CMC, canbe sterilized by autoclave in a solution then combined with rest of thepharmaceutical composition that is prepared aseptically or terminallysterilized.

Some aspects of exemplary embodiments of methods of preparation of theinvention are shown in Tables 4-7 and 23-27 and FIGS. 4-12 and 15 whichdescribe aspects of the preparation methods for exemplary fulvestrantformulations.

TABLE 23 Target Formulation (mg/mL) B E I J K L Fulvestrant 50 50 50 5050 100 Polysorbate 80 5 5 5 5 5 5 PVP 12K 0.8 0.8 0.8 0.8 0.8 0.8 NaCl —— 9 9 9 9 Phosphate — — — 10 mM 10 mM 10 mM buffer WFI q.s. to q.s. toq.s. to q.s. to q.s. to volume q.s. to volume Starting API Un-milledUn-milled API Un-milled API Un-milled API Un-milled API Un-milled API(PSD via laser API L D Dv90: 780 L D Dv90: 780 L D Dv90: 1890 L D Dv90:1890 L D Dv90: 1890 diffraction) L D Dv90: microns microns micronsmicrons microns 780 Manufacturing API size API size API size API sizeAPI size reduction API size reduction by process reduction reduction byreduction by reduction by by HSM followed HSM followed by by HSM HSMfollowed HSM followed HSM followed by HPH in the HPH in the presence byHPH by HPH, then by HPH in the presence of salts, of salts subsequentsalt presence of then further HSM addition salts Process End L D Dv90:Total 15 min Total 42 min Total 45 min Total 45 min HSM Total 25 min HSMat Point Targets 143 HSM at HSM at HSM at at ~25,000 rpm (PSD via lasermicron ~20,000 rpm ~20,000 rpm ~25,000 rpm ~25,000 rpm (L D Dv90:<~80diffraction) HSM: (L D Dv90:<~80 (L D Dv90:<~40 (L D Dv90:<~50 (L DDv90:<~50 micron) Total 15 min micron) micron) micron) micron) L D Dv90:13.8 at HPH: 15 passes L D Dv90: 12.6 L D Dv90: 11.8 L D Dv90: 4.7microns ~20,000 rpm in reverse flow micron micron micron HPH: 15 passesin through z5 HPH: 30 passes HPH: 3 passes HPH: 12 passes in parallelflow through nozzle at in parallel flow in parallel flow parallel flowz8 nozzle at ~30,000 psi ~30,000 psi through z5 through z5 through z5nozzle at L D Dv90: 11.1 nozzle at nozzle at ~40,000 psi to micron~40,000 psi ~40,000 psi L D Dv90: ~8 micron then additional 5 min HSM at~25,000 rpm

TABLE 24 Target Formulation (mg/mL) L3F L6 F003a F003b F004a F003eFulvestrant 100  100  100  100  100  100  Polysorbate 80 5 5 5 5 5 5 PVP12K   0.8   0.8 — — — — NaCl 9 9 — — — — Phosphate 10 mM 10 mM — — 9 —buffer Dextrose — — 50  50  — 50  WFI q.s. to q.s. to q.s. to q.s. toq.s. to q.s. to Starting API Un-milled Un-milled Un-milled API Un-milledAPI Un-milled API Jet-milled (PSD via laser API API L D Dv90: L D Dv90:240 L D Dv90: 240 API diffraction) L D Dv90: 240 micron micron micronManufacturing API size API size API size API size API size API sizeprocess reduction reduction by reduction by reduction by reduction bydispersed by HSM HSM HSM (F001e), HSM followed HSM followed by HSM thenby HPH, then by HPH, then and subsequent subsequent subsequentsonication/ dextrose dextrose NaCl addition vortex addition additionProcess End L D Dv90: L D Dv90: L D Dv90: Total 15 min Total 15 min L DDv90: Point Targets 14.7 17.6 micron 13.6 micron HSM at HSM at 12.2 (PSDvia laser micron and and L D Dv50: ~25,000 rpm to ~25,000 rpm to microndiffraction) and L D Dv50: 6.9 5.7 micron target target HSM: L D Dv50:micron HSM: Total L D Dv90:<~40 L D Dv90:<~40 Total 5 min 5.9 HSM: Total60-120 min micron micron at micron >120 min at at L D Dv90: 15.1 L DDV90: 15.1 ~25,000 rpm HSM: ~25,000-30,000 rpm ~25,000 rpm micron micronto Total before HPH: 15 passes HPH: 15 passes L D Dv90: >120 mindextrose in parallel flow in parallel flow 12.6 at addition to throughz5 through z5 micron by ~25,000-30,000 rpm L D Dv90: 13.0 nozzle atnozzle at sonication/ micron ~40,000 psi ~40,000 psi vortex beforedextrose before NaCl addition to addition to L D Dv90: 12.1 L D Dv90:micron 12.2 micron pH = 7.3 pH = 7.5

TABLE 25 Target Formulation (mg/mL) F003k2 F003k3 F003l F005a2Fulvestrant 100 100 100 100 Polysorbate 80 5 5 5 5 Dextrose 50 50 50 —Mannitol — — — 50 WFI q.s. to q.s. to q.s. to volume q.s. to volumeStarting API Jet-mill API Jet-mill API Jet-mill API L D Dv90: Un-milledAPI L D Dv90: (PSD via laser L D Dv90: 7-8 L D Dv90: 7-8 7-13 micron 240micron diffraction) micron micron Manufacturing API dispersed APIdispersed by API dispersed by HSM API size reduction by process by HSM,then HSM then size (F003i, f, j). Suspension HSM (F001e), thensubsequent reduction by HPH lyophilized, reconstituted mannitoladdition. dextrose in the presence of then composited Suspensionlyophilized, addition dextrose reconstituted then composited Process EndL D Dv90: 6.7 Total 5 min HSM Total 5 min HSM at L D Dv90: 13.6 micronPoint Targets micron after at ~25,000 rpm for and L D Dv50: 5.7 micron(PSD via laser dextrose ~25,000 rpm dispersing each HSM: Total 60-120min. diffraction) addition (Dv90: 9.2 individual API lot at HSM: Total 5min micron) for F003i, f, j before ~25,000 rpm before at dispersing APIlyophilization, L D Dv90: mannitol addition to ~25,000 rpm L D Dv90:13.3 7.0, 12.9, 7.3 micron L D Dv90: 13.2 micron micron HPH: 9 Afterreconstitution, (F005a) passes in parallel L D Dv90: 121, 113, 113 Afterlyophilization, flow through z5 micron. reconstitution, composite nozzleat Composite F003l, F005a2, Dv90: 18.4 ~40,000 psi; L D Dv90: 112 micronmicron dextrose co- processed

TABLE 26 Target Formulation (mg/mL) F005b1 F005c2 F005c3 F005d1 F015a1F015a3 Fulvestrant 100 100 100 100 100 100 Polysorbate 80 5 5 5 5 25 25Mannitol 50 50 50 50 50 50 WFI q.s. to q.s. to q.s. to q.s to q.s. toq.s. to Starting API Jet-mill API Jet-mill Jet-mill API Jet-mill APIJet-mill API Jet-mill API (PSD via laser L D Dv90: 7-8 API L D Dv90: 7-8L D Dv90: 7-8 L D Dv90: 7-8 L D Dv90: 7-8 diffraction) micron L D Dv90:micron micron micron micron 7-8 micron Manufacturing API API LyophilizedAPI size API Lyophilized process dispersed by dispersed F005c2 reductionby dispersed by F015a1 HSM in the by HSM HSM followed HSM in thepresence of then size by HPH, then presence of mannitol reductionsubsequent mannitol by HPH in mannitol the addition presence of mannitolProcess End L D Dv90: Total 5 min After To total 5 min L D Dv90: AfterPoint Targets 7.9 HSM at reconstitution, HSM at 6.9 reconstitution, (PSDvia laser micron ~25,000 rpm L D Dv90: ~25,000 rpm for micron L D Dv90:diffraction) HSM: Total for 112 micron dispersing API HSM: Total 22.7 5min at dispersing L D Dv90: ~7 5 min at micron ~25,000 rpm API micron~25,000 rpm (L D Dv90: HPH with 15 ~7 micron) passes in parallel To HPHflow through z5 with 15 nozzle at passes in ~40,000 psi parallelresulted in flow Dv90: through z5 ~16 micron nozzle at (F001h4) ~40,000psi L D Dv90: 4.0 resulted in micron after L D Dv90: mannitol 17.2micron addition pH = 7.1 pH = 7.1

TABLE 27 Target Formulation (mg/mL) F015a4 F017a1 F017a3 F005g4 F005g5Fulvestrant 100 100 100 100 100 Polysorbate 80 25 15 15 5 5 Mannitol 5050 50 50 50 WFI q.s. to q.s. to q.s. to q.s. to q.s. to Starting APIJet-mill API Jet-mill API Jet-mill API Recrystallized API Recrystallized(PSD via laser L D Dv90: 7-8 L D Dv90: 7-8 L D Dv90: 7-8 L D Dv90: 18API diffraction) micron micron micron micron L D Dv90: 18 micronManufacturing F015a3 gamma API dispersed by Lyophilized, API dispersedby Lyophilized process irradiated at 35 HSM in the gamma HSM in theF005g4 kGy presence of irradiated (35 presence of mannitol KGy) F017a1mannitol Process End After L D Dv90: 7.2 After Total 5 min HSM at PointTargets reconstitution, micron reconstitution, ~25,000 rpm for (PSD vialaser L D Dv90: 22.7 HSM: Total 5 min L D Dv90: 31.9 dispersing APIdiffraction) micron at micron (L D Dv90: ~20 ~25,000 rpm micron) L DDv90: ~10 micron after HPH with 9 passes in parallel flow through z5nozzle at ~40,000 psi Final L D Dv90: 7.5 micron after concentration

D. Pharmacokinetics

In certain embodiments of the invention, the pharmaceutical compositionsare bioequivalent to the commercial pharmaceutical composition,FASLODEX™. The single dose PK parameters in postmenopausal advancedbreast cancer patients administered FASLODEX™ dosed intramuscularly with500 mg with an additional dose at day 15 are reported as, in geometricmean and coefficient of variation (%), Cmax 25.1 (35.3) ng/mL, Cmin 16.3(25.9) ng/mL, and AUC 11,400 (33.4) ng·hr/mL.

In further embodiments of the invention, the 90% confidence intervals(CI) of the relative mean C_(max), AUC_((0-t)) and AUC_((0-∞)) of thepharmaceutical composition of the invention is within 80% to 125% of therelative mean C_(max), AUC_((0-t)) and AUC_((0-∞)), respectively, ofFASLODEX™. In yet further embodiments of the invention, the 90%confidence intervals (CI) of the relative mean C_(max), AUC_((0-t)) andAUC_((0-∞)) of the pharmaceutical composition of the invention is within80% to 125% of the relative mean C_(max), AUC_((0-t)) and AUC_((0-∞)),respectively, of FASLODEX™ in the fasting state. In still furtherembodiments of the invention, the 90% confidence intervals (CI) of therelative mean C_(max), AUC_((0-t)) and AUC_((0-∞)) of the pharmaceuticalcomposition of the invention is within 80% to 125% of the relative meanC_(max), AUC_((0-t)) and AUC_((0-∞)), respectively, of FASLODEX™ in thefed state.

In other embodiments of the invention, the 90% confidence intervals (CI)of the relative mean C_(max), AUC_((0-t)) and AUC_((0-∞)) of thepharmaceutical composition of the invention having a fulvestrantconcentration of 100 mg/mL is within 80% to 125% of the relative meanC_(max), AUC_((0-t)) and AUC_((0-∞)), respectively, of FASLODEX™. Instill other embodiments of the invention, the 90% confidence intervals(CI) of the relative mean C_(max), AUC_((0-t)) and AUC_((0-∞)) of thepharmaceutical composition of the invention having a fulvestrantconcentration of 100 mg/mL is within 80% to 125% of the relative meanC_(max), AUC_((0-t)) and AUC_((0-∞)), respectively, of FASLODEX™ in thefasting state. In yet other embodiments of the invention, the 90%confidence intervals (CI) of the relative mean C_(max), AUC_((0-t)) andAUC_((0-∞)) of the pharmaceutical composition of the invention having afulvestrant concentration of 100 mg/mL is within 80% to 125% of therelative mean C_(max), AUC_((0-t)) and AUC_((0-∞)), respectively, ofFASLODEX™ in the fed state.

In particular embodiments of the invention, the pharmaceuticalcomposition has the single dose and multiple dose pharmacokineticparameters shown in Tables 28 and 29. Table 28 shows pharmacokineticparameters for 500 mg dosage of pharmaceutical compositions of thedisclosure. For the data labeled “Single Dose” in Table 28, thefulvestrant blood plasma concentration data are shown for a 500 mginitial dose with an additional 500 mg dose given on day 15. For thedata labeled “Multiple Dose Steady State” in Table 28, the fulvestrantblood plasma concentration data are shown for measurement at month 3,after a 500 mg dosage on days 1, 15, 20, and once monthly thereafter.Table 29 shows pharmacokinetic parameters for a single 250 mg dosage ofpharmaceutical compositions of the disclosure. In Table 29, data areexpressed as geometric mean (CV %), except for T_(max), which is shownas a median value with a range indicated in parentheses.

TABLE 28 C_(max) (ng/mL) C_(min) (ng/mL) AUC (ng · hr/mL) Single Dose¹ 20.08-31.375 13.04-20.375  9,120-14,250 Multiple Dose 22.4-35.09.76-15.25 10,480-16,375 Steady State²

TABLE 29 I II III IV V VI VII C_(max) 8.20 4.76 8.2   4-8.5 11.8 8.3 8-12 (μg/L) (63.8) (68.1) (6.6) (8.8) C_(min) 2.62 2.38 2.6 2.0-3.0(μg/L) (33.4) (47.7) T_(max) 6.97 8.8 7 6-9 4.2 4.6 4-5 (days)(1.86-7.95) (6.97-12.0) (8.3) (11.2) AUC₂₈ 148 88.4 148  80-150 369 333325-375 (μg · day/L) (45.3) (47.3) (4.1) (3.0)

In particular embodiments, a dose of about 500 mg of a fulvestrantpharmaceutical composition of the invention is bioequivalent to 500 mgof the commercial pharmaceutical composition, FASLODEX™. In certainembodiments, a dose of less than 500 mg of a fulvestrant pharmaceuticalcomposition of the invention is bioequivalent to 500 mg of thecommercial pharmaceutical composition, FASLODEX™. In furtherembodiments, a dose of about 400 to 450 mg of a fulvestrantpharmaceutical composition of the invention is bioequivalent to 500 mgof the commercial pharmaceutical composition, FASLODEX™. In stillfurther embodiments, a dose of about 350 to 400 mg of a fulvestrantpharmaceutical composition of the invention is bioequivalent to 500 mgof the commercial pharmaceutical composition, FASLODEX™. In yet furtherembodiments, a dose of about 300 to 350 mg of a fulvestrantpharmaceutical composition of the invention is bioequivalent to 500 mgof the commercial pharmaceutical composition, FASLODEX™. In even furtherembodiments, a dose of about 250 to 300 mg of a fulvestrantpharmaceutical composition of the invention is bioequivalent to 500 mgof the commercial pharmaceutical composition, FASLODEX™.

In other embodiments of the invention, a 500 mg dose of a pharmaceuticalcomposition of the invention provides 90% confidence intervals (CI) ofthe relative mean C_(max), AUC_((0-t)) and AUC_((0-∞)) within 80% to125% of the relative mean C_(max), AUC_((0-t)) and AUC_((0-∞)),respectively, of a 500 mg dose of FASLODEX™.

In other embodiments of the invention, a dose of less than 500 mg of apharmaceutical composition of the invention provides 90% confidenceintervals (CI) of the relative mean C_(ma), AUC_((0-t)) and AUC_((0-∞))within 80% to 125% of the relative mean C_(max), AUC_((0-t)) andAUC_((0-∞)), respectively, of a 500 mg dose of FASLODEX™.

In some embodiments of the invention, fulvestrant pharmaceuticalcompositions of the invention can be administered as a singleintramuscular injection, with the 90% confidence intervals (CI) of therelative mean Cmax, AUC(0-t) and AUC(0-∞) of fulvestrant is within 80%to 125% of the relative mean Cmax, AUC(0-t) and AUC(0-∞), respectively,of fulvestrant after administration of 500 mg of fulvestrant in the formof FASLODEX™ administered intramuscularly as two 5 mL injections. Infurther embodiments, such fulvestrant pharmaceutical compositionsadministered as a single intramuscular injection comprise a dose ofabout 500 mg of fulvestrant. In yet further embodiments, suchfulvestrant pharmaceutical compositions administered as a singleintramuscular injection comprise a dose of about 500 mg of fulvestrantin an injection volume of about 3.0 mL to about 5.0 mL, about 3.5 mL toabout 4.5 mL, or about 4.0 mL.

In certain embodiments of the invention, the 90% confidence intervals(CI) of the relative mean AUC_((0-t)), relative mean AUC_((0-∞)), orboth of fulvestrant pharmaceutical compositions of the invention iswithin 80% to 125% of the relative mean AUC_((0-t)) and relative meanAUC_((0-∞)), respectively, of FASLODEX™, and the relative mean Cmax offulvestrant pharmaceutical compositions of the invention is less than80% of the relative mean Cmax of FASLODEX™. It is believed that suchembodiments may provide benefits by providing a therapeutically effectamount of fulvestrant exposure to a subject while reducing the degree ofone or more Cmax-driven side-effects or toxicities in comparison to thedegree of side-effects or toxicities experienced by a subject fromreceiving a therapeutically effective amount of fulvestrant exposurefrom one or more dosages of FASLODEX™.

In some embodiments of the invention, the 90% confidence intervals (CI)of the relative mean AUC_((0-t)), relative mean AUC_((0-∞)), or both offulvestrant pharmaceutical compositions of the invention is within 80%to 125% of the relative mean AUC_((0-t)) and relative mean AUC_((0-∞)),respectively, of FASLODEX™, and the relative mean Cmax of fulvestrantpharmaceutical compositions of the invention is less than 80%, less than75%, less than 70%, less than 65%, less than 60%, less than 55%, lessthan 50%, less than 45%, or less than 40% of the relative mean Cmax ofFASLODEX™. In further embodiments, such fulvestrant pharmaceuticalcompositions are administered as a single intramuscular injection andcomprise a dose of about 500 mg of fulvestrant at a concentration ofabout 100 mg/mL.

In yet further embodiments of the invention, the 90% confidenceintervals (CI) of the relative mean AUC_((0-t)), relative meanAUC_((0-∞)), or both of fulvestrant pharmaceutical compositions of theinvention is within 80% to 125% of the relative mean AUC_((0-t)) andrelative mean AUC_((0-∞)), respectively, of FASLODEX™, and the relativemean Cmax of fulvestrant pharmaceutical compositions of the invention isless than 80%, less than 75%, less than 70%, less than 65%, less than60%, less than 55%, less than 50%, less than 45%, or less than 40% ofthe relative mean Cmax of FASLODEX™ in the fasting state. In furtherembodiments, such fulvestrant pharmaceutical compositions areadministered as a single intramuscular injection and comprise a dose ofabout 500 mg of fulvestrant at a concentration of about 100 mg/mL.

In still further embodiments of the invention, the 90% confidenceintervals (CI) of the relative mean AUC_((0-t)), relative meanAUC_((0-∞)), or both of fulvestrant pharmaceutical compositions of theinvention is within 80% to 125% of the relative mean AUC_((0-t)) andrelative mean AUC_((0-∞)), respectively, of FASLODEX™, and the relativemean Cmax of fulvestrant pharmaceutical compositions of the invention isless than 80%, less than 75%, less than 70%, less than 65%, less than60%, less than 55%, less than 50%, less than 45%, or less than 40% ofthe relative mean Cmax of FASLODEX™ in the fed state. In furtherembodiments, such fulvestrant pharmaceutical compositions areadministered as a single intramuscular injection and comprise a dose ofabout 500 mg of fulvestrant at a concentration of about 100 mg/mL.

In some embodiments of the invention, the 90% confidence intervals (CI)of the relative mean AUC_((0-t)), relative mean AUC_((0-∞)), or both offulvestrant pharmaceutical compositions of the invention is within 80%to 125% of the relative mean AUC_((0-t)) and relative mean AUC_((0-∞)),respectively, of FASLODEX™, and the relative mean Cmax of fulvestrantpharmaceutical compositions of the invention is about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, within about 45% to about 55%, within about 55% to about65%, within about 65% to about 75%, within about 50% to about 60%,within about 60% to about 70%, or within about 70% to about 80% of therelative mean Cmax of FASLODEX™. In further embodiments, suchfulvestrant pharmaceutical compositions are administered as a singleintramuscular injection and comprise a dose of about 500 mg offulvestrant at a concentration of about 100 mg/mL.

In yet further embodiments of the invention, the 90% confidenceintervals (CI) of the relative mean AUC_((0-t)), relative meanAUC_((0-∞)), or both of fulvestrant pharmaceutical compositions of theinvention is within 80% to 125% of the relative mean AUC_((0-t)) andrelative mean AUC_((0-∞)), respectively, of FASLODEX™, the relative meanCmax of fulvestrant pharmaceutical compositions of the invention isabout 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, within about 45% to about 55%,within about 55% to about 65%, within about 65% to about 75%, withinabout 50% to about 60%, within about 60% to about 70%, or within about70% to about 80% of the relative mean Cmax of FASLODEX™ in the fastingstate. In further embodiments, such fulvestrant pharmaceuticalcompositions are administered as a single intramuscular injection andcomprise a dose of about 500 mg of fulvestrant at a concentration ofabout 100 mg/mL.

In still further embodiments of the invention, the 90% confidenceintervals (CI) of the relative mean AUC_((0-t)), relative meanAUC_((0-∞)), or both of fulvestrant pharmaceutical compositions of theinvention is within 80% to 125% of the relative mean AUC_((0-t)) andrelative mean AUC_((0-∞)), respectively, of FASLODEX™, and the relativemean Cmax of fulvestrant pharmaceutical compositions of the invention isabout 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, within about 45% to about 55%,within about 55% to about 65%, within about 65% to about 75%, withinabout 50% to about 60%, within about 60% to about 70%, or within about70% to about 80% of the relative mean Cmax of FASLODEX™ in the fedstate. In further embodiments, such fulvestrant pharmaceuticalcompositions are administered as a single intramuscular injection andcomprise a dose of about 500 mg of fulvestrant at a concentration ofabout 100 mg/mL.

E. Methods of Treatment

In further embodiments, the invention is directed to methods oftreatment comprising administration of a pharmaceutically effectiveamount of any of the fulvestrant pharmaceutical compositions describedherein to a patient in need thereof. In particular embodiments, theinvention is directed to a method of treating breast cancer, comprisingadministering a pharmaceutically acceptable amount of any of thefulvestrant pharmaceutical compositions described herein. In certainembodiments, the breast cancer is metastatic breast cancer. In otherembodiments of the invention, the breast cancer is hormone receptor(HR)-positive breast cancer. In still other embodiments of theinvention, the invention is directed to a method of treating hormonereceptor (HR)-positive breast cancer in a post-menopausal womancomprising administration of a pharmaceutically effective amount of anyof the fulvestrant pharmaceutical compositions described herein. In yetother embodiments, the invention is directed to a method of treatinghormone receptor (HR)-positive breast cancer in a post-menopausal womanwith disease progression following antiestrogen therapy comprisingadministration of a pharmaceutically effective amount of any of thefulvestrant pharmaceutical compositions described herein. In yet furtherembodiments, the invention is directed to a method of treatingHR-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer in a woman with disease progressionafter endocrine therapy.

In particular embodiments of the invention, a fulvestrant pharmaceuticalcomposition as described herein is administered on days 1, 15, 29, andonce monthly thereafter. In further embodiments of the invention, a 500mg dose of any of the fulvestrant pharmaceutical compositions asdescribed herein is administered on days 1, 15, 29, and once monthlythereafter. In still further embodiments of the invention, a 250 mg doseof any of the fulvestrant pharmaceutical compositions as describedherein is administered on days 1, 15, 29, and once monthly thereafter.

In certain embodiments of the invention, a fulvestrant pharmaceuticalcomposition as described herein is administered as a single injection.In other embodiments of the invention, a 500 mg dose of any of thefulvestrant pharmaceutical compositions as described herein isadministered as a single injection. In yet other embodiments of theinvention, a 500 mg dose of any of the fulvestrant pharmaceuticalcompositions as described herein is administered as a single 5 mLinjection. In further embodiments of the invention, a 500 mg dose of anyof the fulvestrant pharmaceutical compositions as described herein isadministered as a single 4 mL injection. In yet further embodiments, a500 mg dose of any of the fulvestrant pharmaceutical compositions asdescribed herein is administered as a single 3 mL injection. In stillother embodiments of the invention, a 250 mg dose of any of thefulvestrant pharmaceutical compositions as described herein isadministered as a single injection. In further embodiments of theinvention, a 250 mg dose of any of the fulvestrant pharmaceuticalcompositions as described herein is administered as a single 2.5 mLinjection. In yet further embodiments of the invention, a 250 mg dose ofany of the fulvestrant pharmaceutical compositions as described hereinis administered as a single 5 mL injection.

In particular embodiments of the invention, a fulvestrant pharmaceuticalcomposition as described herein is administered as two injections. Infurther embodiments of the invention, a 500 mg dose of any of thefulvestrant pharmaceutical compositions as described herein isadministered as two injections. In still further embodiments of theinvention, a 500 mg dose of any of the fulvestrant pharmaceuticalcompositions as described herein is administered as two 5 mL injections.In yet further embodiments of the invention, a 500 mg dose of any of thefulvestrant pharmaceutical compositions as described herein isadministered as two 2 mL injections, two 2.5 mL injections, two 3 mLinjections, two 3.5 mL injections, or two 4 mL injections. In otherembodiments of the invention, a 250 mg dose of any of the fulvestrantpharmaceutical compositions as described herein is administered as twoinjections. In yet other embodiments of the invention, a 250 mg dose ofany of the fulvestrant pharmaceutical compositions as described hereinis administered as two 2.5 mL injections.

The fulvestrant pharmaceutical compositions described herein may beadministered alone, or in combination with one or more additionaltherapeutic agents as defined herein. An additional therapeutic agentmay be used to treat one or more core symptoms and/or comorbiditiesassociated with cancer in general or breast cancer in particular. In oneaspect, fulvestrant is formulated (and administered) with at least onetherapeutic agent as a fixed dose. In another aspect, fulvestrant isformulated (and administered) separately from the therapeutic agent(s).

Some examples of therapeutic agents that may be used in combination withfulvestrant include, but are not limited to, e.g., a EGFR kinaseinhibitor, a PDGFR kinase inhibitor, a FGFR kinase inhibitor, or any ofthe other cytotoxic, chemotherapeutic, antihormonal, anti-angiogenic,antiproliferative, pro-apoptotic, anti-HER2, radiation or aradiopharmaceutical, signal transduction inhibitors, or otheranti-cancer agents or treatments. Examples of particular agents that canbe used in combination with the fulvestrant pharmaceutical compositionsof the disclosure include palbociclib, letrozole, anastrozole,doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil. Inother embodiments, therapeutic agents that may be used in combinationwith fulvestrant include, but are not limited to, agents or treatmentsfor one or more of pain, nausea, emesis, hot flushes, constipation, anddizziness.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the disclosureand that such changes and modifications can be made without departingfrom the spirit of the disclosure. It is, therefore, intended that thefollowing examples and appended claims cover all such equivalentvariations as fall within the true spirit and scope of the disclosure.

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, in its entirety.

EXAMPLES Example: Preparation of Fulvestrant PharmaceuticalCompositions/Variants

Some exemplary fulvestrant pharmaceutical compositions were preparedwith 50 mg/mL and 100 mg/mL concentrations of fulvestrant in aqueoussuspensions. Tables 1-20 show aspects of the pharmaceutical compositionsof the pharmaceutical compositions and the methods of preparation ofsome of the pharmaceutical compositions, also referred to asformulations, variants, or Lots in the Tables. Tables 4-7 and 23-27 andFIGS. 4-12 and 15 show aspects of the methods of preparation used toprepare some of the pharmaceutical compositions.

Where indicated in the Tables and Figures, the formulations B, E, I, J,K, L, L3F, L6, F003a, F003b, F003e, F004a, F003k2, F003k3, F005a2,F003l, F005b1, F015a1, F015a3, F005d1, F005c3, F005g5 tested in Studies1-3 below were prepared via one or more of process steps of (1) lowshear mixing, indicated in the Tables 23-27 and FIGS. 4-12 as “Mix” or“Mix with Vortex Mixer” steps; (2) high shear mixing, indicated as “HSM”or “Homogenize” steps; (3) high pressure homogenization, indicated as“HPH” or “Process with Nano DeBee” steps; (4) concentration viasupernatant removal; and (5) application of sonication. Where indicated,supernatant removal was performed by phase separating the pharmaceuticalcomposition and withdrawing the desired amount of supernatant toconcentrate the suspensions to the target concentrations of fulvestrant,either 50 mg/mL or 100 mg/mL, depending on the pharmaceuticalcomposition. Where indicated, phase separation was performed byovernight settling in a clear glass centrifuge tube. Application ofcentrifuge for phase separation could also be utilized.

Fulvestrant active pharmaceutical ingredient (which may also be referredto as “API” herein and in the Tables and Figures) was obtained inun-milled forms or in milled, micronized, or recrystallized forms fromcommercial suppliers. As-obtained particle size distributions forun-milled API varied from an LD Dv(90) of about 240 microns to an LDDv(90) of about 2130 microns. As-obtained particle size distributionsfor milled, micronized, and recrystallized API varied from an LD Dv(90)of about 7 microns to an LD Dv(90) of about 18 microns. Fulvestrant APImay be obtained in various particle size distributions from commercialsources and processed as described elsewhere herein to achieve thedesired particle size distributions. Particle size distributions can bemonitored throughout the processing steps through analysis of samples asdescribed elsewhere herein.

Where indicated in the Tables and Figures, the formulations B, E, I, J,K, L, L3F, L6, F003a, F003b, F003e, F004a, F003k2, F003k3, F005a2,F003l, F005b1, F015a1, F015a3, F005d1, F005c3, F005g5 tested in Studies1-3 below were prepared via high shear mixing (HSM) steps. Thepreparation of formulations can be performed with an IKA T10 BasicDisperser with an IKA S10N-10G dispersing tool. At the speeds indicated(˜20,000 to 30,000 rpm), the mixture of fulvestrant and suspensionvehicle was processed in cycles until the total processing timeindicated was reached. Between each cycle, a formulation was vortexed at˜3000 rpm for 30 seconds then sonicated for 1 minute to remove or reducefoam generated during the high shear mixing by the disperser.Formulations were also rested as needed in between cycles at roomtemperature to allow the disperser to cool down and avoid overheating ofthe product and the equipment. Sonication was performed with a Branson3800 Ultrasonic Bath (Branson Ultrasonics Corp., Danbury, Conn.) at afrequency of 40 kHz. Other mixing and ultrasonic apparatuses may also beused to achieve mixing and particle size distribution as desired.

In some embodiments, high pressure homogenization was performed. Incertain embodiments, high pressure homogenization (HPH) steps wereperformed with a Nano DeBEE High Pressure Homogenizer (BEEInternational, South Easton, Mass.) in a Labconco XPert Filtered BalanceSystem (Model 3950630) (Labconco, Kans. City, Mo.), installed the 100 mlsample holder and Z5 nozzle in parallel flow configuration on Nano DeBEEHigh Pressure Homogenizer. The homogenizer was primed with filing wateruntil the process pressure reached the processing pressure as indicatedin the Tables and Figures. Water was removed from the system using theplunger to minimize the dilution of the batch by the residual primingwater. Approximately ˜50 ml of the suspension for HPH processing wasloaded from the 50 mL clear Pyrex glass bottle on Nano DeBEE HighPressure Homogenizer. The Nano DeBEE was run in continuous mode untilthe pressure reached the indicated target processing pressure. Thesuspension was then processed for the indicated number passes at theprocessing pressure. To avoid losing the prime of the system andconsequently the processing pressure, only total ˜40 mL (8 strokes of ˜5mL per stroke) of the suspension was processed and collected from eachpass. The 40 mL suspension was then loaded back to the reservoir for thesuspension to be processed in the next pass. After the processing wascompleted, 40 ml fine suspension was collected in a 100 mL clear Pyrexglass bottle by running Nano DeBEE High Pressure Homogenizer until nosample was pumped out. In certain embodiments, high pressurehomogenization was performed with other apparatuses at processingpressures ranging from about 5,000 psi to about 45,000 psi. Other highpressure homogenization apparatuses may also be used to achieve thedesired particle size distributions described herein.

Some formulations for Study 3 below were lyophilized and reconstitutedwith sterile water for injection, USP prior to administration, asindicated in the Example below.

References to “Assay” refers to high-performance liquid chromatography(HPLC) measurement of the fulvestrant concentration of thepharmaceutical composition at intermediate processing steps or in finalresult as prepared. The “Assay” results are given in absolute measuredmg/mL or as a percentage (%) or (% LC), where percentages indicate theconcentration of fulvestrant relative to the 50 mg/mL label claim of thecommercially available FASLODEX™ product. Total impurities were alsomeasured and are provided in the figures as a percentage by area (% a/a)where indicated. HPLC was performed with Agilent Technologies Agilent1260 Infinity Quaternary LC module G1311B (Agilent Technologies, SantaClara, Calif.). Other HPLC apparatuses may also be used to analyze thefulvestrant concentrations.

In some aspects, particle size and particle size distributions wereanalyzed with Malvern Mastersizer 3000 (Malvern Instruments Ltd.,Malvern, Worcestershire, UK), with an attached sample dispersion unitwith an in-line sonication probe for agglomerate dispersion prior toanalysis via laser diffraction.

In some aspects, particle size and particle size distributions wereanalyzed with Malvern Morphologi G3 (Malvern Instruments Ltd., Malvern,Worcestershire, UK), to determine circle equivalent (CE) diameters viamicroscopy image capture and analysis.

Measurements of pH were obtained at ambient room temperature with aThermo Scientific Orion Star A211 pH Meter (Thermo Fisher ScientificInc., Waltham, Mass.).

Example: Pharmacokinetic Study 1 of Intramuscular Administration toFemale Dogs

Fulvestrant pharmaceutical compositions B, E, I, J, K, and L wereprepared as described elsewhere herein and in the Figures. A preclinicalstudy was performed to determine the pharmacokinetics of thepharmaceutical compositions following a single intramuscularadministration of 15.4 mg/kg to female dogs. The pharmacokinetics of15.4 mg/kg IM FASLODEX™ (fulvestrant injection, 250 mg/5 mL) were alsodetermined and used for comparison to the three prototype pharmaceuticalcompositions. The 15.4 mg/kg dose used in this study is the canineequivalent, in mg/m², of the maximum dose (500 mg) for human use and wasscaled for use in canine by dividing the dose (based on a 60 kg human)by a canine species conversion factor of 0.54.

Twenty-four non-naïve female beagle dogs were used in the study. Theanimals weighed between approximately 5-10 kg. Animal welfare for thisstudy was in compliance with the U.S. Department of Agriculture's (USDA)Animal Welfare Act (9 Code of Federal Regulations (CFR) Parts 1, 2 and3). The Guide for the Care and Use of Laboratory Animals, Institute ofLaboratory Animal Resources, National Academy Press, Washington, D.C.,was followed. The facility maintained an Animal Welfare Assurancestatement with the National Institutes of Health, Office of LaboratoryAnimal Welfare.

The FASLODEX™ test articles contained a small molecule that was used asreceived and no adjustment was made for purity, salt correction, etc.The FASLODEX™ test articles were gently agitated prior to dispensing anddose delivery. Pharmaceutical Composition B, Pharmaceutical CompositionE, Pharmaceutical Composition I, Pharmaceutical Composition J,Pharmaceutical Composition K, and Pharmaceutical Composition L werestored at room temperature and protected from light prior to use, andgently agitated prior to dispensing and dose delivery.

The animals were not fasted prior to dosing. Each animal received asingle intramuscular (IM) dose of only one of the appropriate testarticle pharmaceutical compositions as outlined in the following studydesign table, Table 30. IM doses were administered with a 20 G needlevia bolus injection into the same large muscle mass (using the Z-trackinjection technique) in the left hind limb of each animal. Attempts weremade for consistent injections between animals [selection of the dosesite (muscle), depth, etc.]. The hair was clipped from the injectionsite prior to dosing. The injection site was marked following dosing andremarked as necessary throughout the study. Specifications for all dosedelivery were recorded and reported in the study report [including, butnot limited to needle gauge/length, syringe size/barrel type withmanufacturer and part number, estimated injection depth into the muscle,approximate duration required to administer the injection; anysubstantial resistance (either flow through the syringe/needle and/orinto the muscle during administration)] was documented.

TABLE 30 Pharmaceutical Composition Fulvestrant Dose Dose No. ofConcentration Level Volume Group Test Article Females (mg/mL) (mg/kg)(mL/kg) 1 FASLODEX ™ 3 50 15.4 0.308 2 Pharmaceutical 3 50 15.4 0.308Composition B 3 Pharmaceutical 3 50 15.4 0.308 Composition E 4FASLODEX ™ 3 50 15.4 0.308 5 Pharmaceutical 3 50 15.4 0.308 CompositionI 6 Pharmaceutical 3 50 15.4 0.308 Composition J 7 Pharmaceutical 3 5015.4 0.308 Composition K 8 Pharmaceutical 3 100 15.4 0.154 Composition L

All animals were observed at least twice a day for morbidity, mortality,injury, and availability of food and water. Any animals in poor healthwere identified for further monitoring and possible euthanasia.

Blood samples were collected at various time intervals to measure theblood plasma concentration of fulvestrant. Blood samples for Groups 1-3were collected predose and at 0.25, 0.5, 1, 2, 4, 8, and 12 (on Day 1);and 24 (on Day 2), 48 (on Day 3), 120 (on Day 6), 192 (on Day 9), 264(on Day 12), 336 (on Day 15), 384 (on Day 17), 456 (on Day 20), 528 (onDay 23), 600 (on Day 26), and 672 (on Day 29) hours postdose. Bloodsamples for Groups 4-8 were collected predose and at 0.25, 0.5, 1, 2, 4,8, and 12 (on Day 1); and 24 (on Day 2), 48 (on Day 3), 72 (on Day 4),96 (on Day 5), 120 (on Day 6), 192 (on Day 9), 264 (on Day 12), 336 (onDay 15), 384 (on Day 17), 528 (on Day 23), and 672 (on Day 29) hourspostdose.

Whole venous blood samples of approximately 2 mL each were collectedfrom a peripheral vein of all animals for determination of fulvestrantexposure. Blood was collected with sodium heparin anticoagulant (glasstube, no gel separator). All blood samples were placed on wet icefollowing collection until centrifuged. Blood was centrifuged at 3500rpm for 7 minutes at 2 to 8° C. Plasma (minimum of 0.8 mL volume) wasseparated from blood cells within 0.75 hours of blood collection andfrozen. Plasma samples were initially placed on dry ice prior to beingstored in the appropriate freezer (−60 to −90° C.). Samples were shippedon dry ice for bioanalytical analysis.

A model independent method was used to determine C_(max) and AUC valuesfrom fulvestrant plasma concentration-time data. Results are shown inTables 31-37 and FIGS. 1B, 2A, 2C, and 3. Table 31 shows thepharmacokinetic data from the 15.4 mg/kg dosages as nominally dosed(based on the target fulvestrant concentration for each pharmaceuticalcomposition). An “Assay %” is shown for the fulvestrant pharmaceuticalcompositions of the present disclosure used in the study. The “Assay %”represents the percentage equivalence of the particular pharmaceuticalcomposition in comparison to the FASLODEX™ label claim fulvestrantconcentration, with “Assay %” values determined via HPLC, measurementsamples taken pre- and post-dose, with one value selected fornormalization. The data in Tables 32-37 are normalized using the “Assay%” values to compare PK results based upon the actual mg/kg offulvestrant administered, assuming linear scaling. FIGS. 1B, 2A, 2C, and3 depict graphs of the dose normalized fulvestrant mean plasmaconcentrations.

TABLE 31 PK parameters based upon the nominal dose 15.4 mg/kg Assay (%)Assay (%) (measured (measured Variant pre-dose) post-dose) (GeometricMean of AUC0-14 d AUC0-28 d Starred value used for n as indicated) Cmax(ng/mL) (hr * ng/mL) (hr * ng/mL) normalization Faslodex 35.0 7015 8917(LW466, n = 9) Faslodex 45.7 7666 9306 (MB122, n = 6) Faslodex 32.0 71779018 (MB948, n = 3) Faslodex 36.9 8149 9817 (MC949, n = 4) Faslodex 37.57408 9195 (All, n = 22) B (n = 3) 8.7 1930 3250 100.0* 138.9 E (n = 3)29.1 5750 8380 93.4* 91.8 I (n = 3) 41.5 8840 12300 95.6* 99.6 J (n = 3)44.8 5750 8100 87.6* 93.6 K (n = 3) 69.7 7540 9630 84.6* 91.2 L (n = 3)63.9 8430 11000 94.1* 97.3 L3F (n = 3) 22.6 5140 7130 83.8* 79.0 L6 (n =3) 24.7 6050 9360 113.9* 113.9 F003a (n = 3) 27.7 5860 8610 95.0* 97.1F003b (n = 3) 32.5 7210 9650 96.3* 97.4 F003e (n = 3) 28.5 6400 9080100.6* 100.5 F004a (n = 3) 31.7 4310 6190 99.8* 100.4 F003k2 (n = 4) 333910 5960 97.8* 100.1 F003k3 (n = 4) 26.8 5430 7060 99.6* 100.7 F005a2(L, n = 3) 19.7 4370 6840 — 93.2* F003l (L, n = 3) 25.1 5510 8680 —99.2* F005b1 (n = 3) 49.7 9420 12100 100.2* — F015a1 (n = 3) 63.6 47507120 103.8* — F015a3 (L, n = 3) 34.4 3850 6000 — 98.6* F005d1 (n = 3)37.9 7180 9910 100.5* 99.2 F005c3 (L, n = 3) 17.7 3680 5820 95.2* —

TABLE 32 PK parameters normalized against the actual dose Cmax Variant(Geometric (ng/mL AUC0-14 d AUC0-28 d Mean of n as per (hr * ng/mL per(hr * ng/mL per indicated) mg/kg) mg/kg) mg/kg) Faslodex (LW466, 2.3 456579 n = 9) Faslodex (MB122, 3.0 498 604 n = 6) Faslodex (MB948, 2.1 466586 n = 3) Faslodex (MC949, 2.4 529 637 n = 4) Faslodex 2.4 481 597(All, n = 22) B (n = 3) 0.6 125 211 E (n = 3) 2.0 400 583 I (n = 3) 2.8600 835 J (n = 3) 3.3 426 600 K (n = 3) 5.3 579 739 L (n = 3) 4.4 582759 L3F (n = 3) 1.8 398 552 L6 (n = 3) 1.4 345 534 F003a (n = 3) 1.9 401589 F003b (n = 3) 2.2 486 651 F003e (n = 3) 1.8 413 586 F004a (n = 3)2.1 280 403 F003k2 (n = 4) 2.2 260 396 F003k3 (n = 4) 1.7 354 460 F005a2(L, n = 3) 1.4 304 477 F003l (L, n = 3) 1.6 361 568 F005b1 (n = 3) 3.2610 784 F015a1 (n = 3) 4.0 297 445 F015a3 (L, n = 3) 2.3 254 395 F005d1(n = 3) 2.4 464 640 F005c3 (L, n = 3) 1.2 251 397

TABLE 33 Comparison of normalized PK parameters against all Faslodexlots Variant Cmax (Geometric Mean of ratio to AUC0-14 d ratio AUC0-28 dratio n as indicated) Faslodex (%) to Faslodex (%) to Faslodex (%)Faslodex (LW466, 93 95 97 n = 9) Faslodex (MB122, 122 103 101 n = 6)Faslodex (MB948, 85 97 98 n = 3) Faslodex (MC949, 98 110 107 n = 4)Faslodex 100 100 100 (All, n = 22) B (n = 3) 23 26 35 E (n = 3) 83 83 98I (n = 3) 116 125 140 J (n = 3) 136 89 101 K (n = 3) 219 120 124 L (n =3) 181 121 127 L3F (n = 3) 72 83 93 L6 (n = 3) 58 72 89 F003a (n = 3) 7883 99 F003b (n = 3) 90 101 109 F003e (n = 3) 75 86 98 F004a (n = 3) 8558 67 F003k2 (n = 4) 90 54 66 F003k3 (n = 4) 72 74 77 F005a2 (L, n = 3)56 63 80 F003l (L, n = 3) 67 75 95 F005b1 (n = 3) 132 127 131 F015a1 (n= 3) 163 62 75 F015a3 (L, n = 3) 93 53 66 F005d1 (n = 3) 100 96 107F005c3 (L, n = 3) 50 52 66

TABLE 34 Comparison of normalized PK parameters against Faslodex lotLW466 Cmax Variant ratio to (Geometric Mean of n Faslodex AUC0-14 dratio AUC0-28 d ratio as indicated) (%) to Faslodex (%) to Faslodex (%)Faslodex (LW466, 100 100 100 n = 9) Faslodex (MB122, 131 109 104 n = 6)Faslodex (MB948, 92 102 101 n = 3) Faslodex (MC949, 106 116 110 n = 4)Faslodex 107 106 103 (All, n = 22) B (n = 3) 25 28 36 E (n = 3) 89 88101 I (n = 3) 124 132 144 J (n = 3) 146 94 104 K (n = 3) 236 127 128 L(n = 3) 194 128 131 L3F (n = 3) 77 87 95 L6 (n = 3) 62 76 92 F003a (n =3) 83 88 102 F003b (n = 3) 97 107 112 F003e (n = 3) 81 91 101 F004a (n =3) 91 62 70 F003k2 (n = 4) 97 57 68 F003k3 (n = 4) 77 78 79 F005a2 (L, n= 3) 60 67 82 F003l (L, n = 3) 72 79 98 F005b1 (n = 3) 142 134 135F015a1 (n = 3) 175 65 77 F015a3 (L, n = 3) 100 56 68 F005d1 (n = 3) 108102 111 F005c3 (L, n = 3) 53 55 69

TABLE 35 Comparison of normalized PK parameters against Faslodex lotMB122 Cmax Variant ratio to (Geometric Mean of n Faslodex AUC0-14 dratio AUC0-28 d ratio as indicated) (%) to Faslodex (%) to Faslodex (%)Faslodex (LW466, 76 92 96 n = 9) Faslodex (MB122, 100 100 100 n = 6)Faslodex (MB948, 70 94 97 n = 3) Faslodex (MC949, 81 106 105 n = 4)Faslodex 82 97 99 (All, n = 22) B (n = 3) 19 25 35 E (n = 3) 68 80 96 I(n = 3) 95 121 138 J (n = 3) 112 86 99 K (n = 3) 180 116 122 L (n = 3)148 117 126 L3F (n = 3) 59 80 91 L6 (n = 3) 47 69 88 F003a (n = 3) 64 8097 F003b (n = 3) 74 98 108 F003e (n = 3) 62 83 97 F004a (n = 3) 69 56 67F003k2 (n = 4) 74 52 65 F003k3 (n = 4) 59 71 76 F005a2 (L, n = 3) 46 6179 F003l (L, n = 3) 55 72 94 F005b1 (n = 3) 108 123 130 F015a1 (n = 3)134 60 74 F015a3 (L, n = 3) 76 51 65 F005d1 (n = 3) 82 93 106 F005c3 (L,n = 3) 41 50 66

TABLE 36 Comparison of normalized PK parameters against Faslodex lotMB948 Cmax Variant ratio to (Geometric Mean of n Faslodex AUC0-14 dratio AUC0-28 d ratio as indicated) (%) to Faslodex (%) to Faslodex (%)Faslodex (LW466, 109 98 99 n = 9) Faslodex (MB122, 143 107 103 n = 6)Faslodex (MB948, 100 100 100 n = 3) Faslodex (MC949, 115 114 109 n = 4)Faslodex 117 103 102 (All, n = 22) B (n = 3) 27 27 36 E (n = 3) 97 86 99I (n = 3) 136 129 143 J (n = 3) 160 91 103 K (n = 3) 257 124 126 L (n =3) 212 125 130 L3F (n = 3) 84 85 94 L6 (n = 3) 68 74 91 F003a (n = 3) 9186 100 F003b (n = 3) 105 104 111 F003e (n = 3) 89 89 100 F004a (n = 3)99 60 69 F003k2 (n = 4) 105 56 68 F003k3 (n = 4) 84 76 79 F005a2 (L, n =3) 66 65 81 F003l (L, n = 3) 79 77 97 F005b1 (n = 3) 155 131 134 F015a1(n = 3) 191 64 76 F015a3 (L, n = 3) 109 54 67 F005d1 (n = 3) 118 100 109F005c3 (L, n = 3) 58 54 68

TABLE 37 Comparison of normalized PK parameters against Faslodex lotMB949 Cmax Variant ratio to (Geometric Mean of n Faslodex AUC0-14 dratio AUC0-28 d ratio as indicated) (%) to Faslodex (%) to Faslodex (%)Faslodex (LW466, 95 86 91 n = 9) Faslodex (MB122, 124 94 95 n = 6)Faslodex (MB948, 87 88 92 n = 3) Faslodex (MC949, 100 100 100 n = 4)Faslodex 102 91 94 (All, n = 22) B (n = 3) 24 24 33 E (n = 3) 84 76 91 I(n = 3) 118 113 131 J (n = 3) 139 81 94 K (n = 3) 223 109 116 L (n = 3)184 110 119 L3F (n = 3) 73 75 87 L6 (n = 3) 59 65 84 F003a (n = 3) 79 7692 F003b (n = 3) 91 92 102 F003e (n = 3) 77 78 92 F004a (n = 3) 86 53 63F003k2 (n = 4) 91 49 62 F003k3 (n = 4) 73 67 72 F005a2 (L, n = 3) 57 5875 F003l (L, n = 3) 69 68 89 F005b1 (n = 3) 134 115 123 F015a1 (n = 3)166 56 70 F015a3 (L, n = 3) 94 48 62 F005d1 (n = 3) 102 88 100 F005c3(L, n = 3) 50 47 62

Example: Pharmacokinetic Study 2 of Intramuscular Administration toFemale Dogs

Fulvestrant pharmaceutical compositions L3F and L6 were prepared asdescribed elsewhere herein and in the Figures. A preclinical study wasperformed to determine the pharmacokinetics of the pharmaceuticalcompositions following a single intramuscular administration of 15.4mg/kg to female dogs. The pharmacokinetics of 15.4 mg/kg IM FASLODEX™(fulvestrant injection, 250 mg/5 mL) were also determined and used forcomparison to the three prototype pharmaceutical compositions. The 15.4mg/kg dose used in this study is the canine equivalent, in mg/m², of themaximum dose (500 mg) for human use and was scaled for use in canine bydividing the dose (based on a 60 kg human) by a canine speciesconversion factor of 0.54.

Nine non-naïve female beagle dogs were used in the study. The animalsweighed between approximately 5-13 kg. Animal welfare for this study wasin compliance with the U.S. Department of Agriculture's (USDA) AnimalWelfare Act (9 Code of Federal Regulations (CFR) Parts 1, 2 and 3). TheGuide for the Care and Use of Laboratory Animals, Institute ofLaboratory Animal Resources, National Academy Press, Washington, D.C.,was followed. The facility maintained an Animal Welfare Assurancestatement with the National Institutes of Health, Office of LaboratoryAnimal Welfare.

The FASLODEX™ test articles contained a small molecule that was used asreceived and no adjustment was made for purity, salt correction, etc.The FASLODEX™ test articles were gently agitated prior to dispensing anddose delivery. Pharmaceutical Compositions L3F and L6 were stored atroom temperature and protected from light prior to use, and gentlyagitated prior to dispensing and dose delivery.

TABLE 38 Fulvestrant Dosage Conc. Dose Volume Dose Group Test Article(mg/kg) (mg/mL) (mg/kg) 1 FASLODEX ™ 15.4 50 0.308 2 Pharmaceutical 15.4100 0.154 Composition L3F 3 Pharmaceutical 15.4 100 0.154 Composition L6

The animals were not fasted prior to dosing. Each animal received asingle intramuscular (IM) dose of only one of the appropriate testarticle pharmaceutical compositions as outlined in the following studydesign table, Table 38. IM doses were administered with a 20 G needlevia bolus injection into the same large muscle mass (using the Z-trackinjection technique) in the left hind limb of each animal. Attempts weremade for consistent injections between animals [selection of the dosesite (muscle), depth, etc.]. The hair was clipped from the injectionsite prior to dosing. The injection site was marked following dosing andremarked as necessary throughout the study. Specifications for all dosedelivery were recorded and reported in the study report [including, butnot limited to needle gauge/length, syringe size/barrel type withmanufacturer and part number, estimated injection depth into the muscle,approximate duration required to administer the injection; anysubstantial resistance (either flow through the syringe/needle and/orinto the muscle during administration)] was documented.

All animals were observed at least twice a day for morbidity, mortality,injury, and availability of food and water. Any animals in poor healthwere identified for further monitoring and possible euthanasia.

Whole venous blood samples of approximately 2 mL each were collectedfrom a peripheral vein of all animals for determination of fulvestrantexposure. Samples were collected at the following target timepoints;predose, 0.25, 0.5, 1, 2, 4, 8, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4),96 (Day 5), 120 (Day 6), 192 (Day 9), 264 (Day 12), 336 (Day 15), 384(Day 17), 528 (Day 23), and 672 (Day 29) hours after administration.Blood was collected with sodium heparin anticoagulant (glass tube, nogel separator). All blood samples were placed on wet ice followingcollection until centrifuged. Blood was centrifuged at 3500 rpm for 7minutes at 2 to 8° C. Plasma (minimum of 0.8 mL volume) was separatedfrom blood cells within 0.75 hours of blood collection and frozen.Plasma samples were initially placed on dry ice prior to being stored inthe appropriate freezer (−60 to −90° C.). Samples were shipped on dryice for bioanalytical analysis.

A model independent method was used to determine C_(max) and AUC valuesfrom fulvestrant plasma concentration-time data. Results are shown inTables 31-37 and FIGS. 2A and 2C. Table 31 shows the pharmacokineticdata from the 15.4 mg/kg dosages as nominally dosed (based on the targetfulvestrant concentration for each pharmaceutical composition). An“Assay %” is shown for the fulvestrant pharmaceutical compositions ofthe present disclosure used in the study. The “Assay %” represents thepercentage equivalence of the particular pharmaceutical composition incomparison to the FASLODEX™ label claim fulvestrant concentration, with“Assay %” values determined via HPLC, measurement samples taken pre- andpost-dose, with one value selected for normalization. The data in Tables32-37 are normalized using the “Assay %” values to compare PK resultsbased upon the actual mg/kg of fulvestrant administered, assuming linearscaling. FIGS. 2A and 2C depict graphs of the dose normalizedfulvestrant mean plasma concentrations.

Example: Pharmacokinetic Study 3 of Intramuscular and IntravenousAdministration to Female Dogs

Fulvestrant formulations F003a, F003b, F004a, F003e, F003k2, F003k3,F005a2, F0031, F005b1, F015a1, F005d1, F005c3, F015a3, F005g5, Del-1S,Del-2S, F005H3, Lot 15, Lot 26, Lot 27, Lot 28, Lot 42, Lot 43, Lot 45,Lot 46, Lot 47, and Lot 48 were prepared as described elsewhere hereinand in the Figures. In some instances, the formulations were preparedusing different processes as indicated, referred to by an alphanumericprocess identifier, such as “Process A1,” “Process A2,” and the like. Afulvestrant pharmaceutical composition for intravenous injection,referred to as batch FV-004/15M, was prepared as described below. Apreclinical study was performed to determine the pharmacokinetics of thepharmaceutical compositions following a single intramuscular (IM)administration of 15.4 mg/kg to female dogs. The pharmacokinetics of15.4 mg/kg IM FASLODEX™ (fulvestrant injection, 250 mg/5 mL) were alsodetermined and used for comparison to the three prototype pharmaceuticalcompositions. The 15.4 mg/kg dose used in this study is the canineequivalent, in mg/m², of the maximum dose (500 mg) for human use and wasscaled for use in canine by dividing the dose (based on a 60 kg human)by a canine species conversion factor of 0.54.

One hundred fifty-six non-naïve female beagle dogs of body weight rangeof 5.65 to 11.40 kilograms were used in the study and assigned to Groups1-48, as shown in Table 39 below.

Animal welfare for this study was in compliance with the U.S. Departmentof Agriculture's (USDA) Animal Welfare Act (9 Code of FederalRegulations (CFR) Parts 1, 2 and 3). The Guide for the Care and Use ofLaboratory Animals, Institute of Laboratory Animal Resources, NationalAcademy Press, Washington, D.C., was followed. The facility maintainedan Animal Welfare Assurance statement with the National Institutes ofHealth, Office of Laboratory Animal Welfare.

TABLE 39 Fulvestrant Dose Dose Group Number of Dose Concentration LevelVolume Number Test Article Females Route (mg/mL) (mg/kg) (mL/kg) 1Faslodex (lot 3 IM 50 15.4 0.308 LW466) 2 Faslodex (lot 3 IM 50 15.40.308 MB122) 3 Faslodex (lot 3 IM 50 15.4 0.308 MB948) 4 FormulationF003a 3 IM 100 15.4 0.154 5 Formulation F003b 3 IM 100 15.4 0.154 6Formulation F004a 3 IM 100 15.4 0.154 7 Formulation F003e 3 IM 100 15.40.154 8 Formulation F003k2 4 IM 100 15.4 0.154 9 Formulation F003k3 4 IM100 15.4 0.154 10 Faslodex (lot 4 IM 50 15.4 0.308 MC949) 11 FormulationF005a2 3 IM 100 15.4 0.154 12 Formulation F003l 4 IM 100 15.4 0.154 13Formulation F005b1 3 IM 100 15.4 0.154 14 Formulation F015a1 3 IM 10015.4 0.154 15 Formulation F005d1 3 IM 100 15.4 0.154 16 FormulationF005c3 4 IM 100 15.4 0.154 17 Formulation F015a3 3 IM 100 15.4 0.154 18Fulvestrant 4 IV 20 2.5 0.125 (batch FV-004/15M) 19 Formulation F005g5 4IM 100 15.4 0.154 20 Formulation Del-1S 4 IM 100 15.4 0.154 21Formulation Del-2S 4 IM 100 15.4 0.154 22 Formulation F005H3 3 IM 10015.4 0.154 23 Lot 15, by Process 4 IM 100 15.4 0.154 E1 24 Lot 15, byProcess 3 IM 100 15.4 0.154 E2 25 Lot 26, by Process F1 3 IM 100 15.40.154 26 Lot 26, by Process F2 3 IM 100 15.4 0.154 27 Lot 26, by ProcessF3 3 IM 100 15.4 0.154 28 Lot 26, by Process F4 3 IM 100 15.4 0.154 29Lot 26, by Process J1 3 IM 100 15.4 0.154 30 Lot 26, by Process J2 3 IM100 15.4 0.154 31 Lot 26, by Process J3 3 IM 100 15.4 0.154 32 Lot 26,by Process J4 3 IM 100 15.4 0.154 33 Lot 42, by Process G1 3 IM 100 15.40.154 34 Lot 42, by Process G2 3 IM 100 15.4 0.154 35 Lot 43, by ProcessH1 3 IM 100 15.4 0.154 36 Lot 43, by Process H2 3 IM 100 15.4 0.154 37Lot 27, by Process A1 3 IM 100 15.4 0.154 38 Lot 27, by Process A2 3 IM100 15.4 0.154 39 Lot 27, by Process A3 3 IM 100 15.4 0.154 40 Lot 27,by Process A4 3 IM 100 15.4 0.154 41 Lot 28, by Process B1 3 IM 100 15.40.154 42 Lot 28, by Process B2 3 IM 100 15.4 0.154 43 Lot 28, by ProcessB3 3 IM 100 15.4 0.154 44 Lot 28, by Process B4 3 IM 100 15.4 0.154 45Lot 45, by Process C1 3 IM 100 15.4 0.154 46 Lot 46 3 IM 100 15.4 0.15447 Lot 47 3 IM 100 15.4 0.154 48 Lot 48 3 IM 100 15.4 0.154

Pharmaceutical Compositions F003a, F003b, F004a, F003e, F003k2, F003k3,F005a2, F0031, F005b1, F015a1, F005d1, F005c3, F015a3, FV-004/15M,Del-1S, and Del-2S were stored at room temperature and protected fromlight prior to use, and gently agitated via inversion prior todispensing and dose delivery. If visible clumps of material were seen onthe vial inside wall or inner seal of the vial cap after 3 minutes ofinversion, the tightly capped vial was vortexed at moderate intensityand unlimited duration until clumps were not visible. FASLODEX™ wassupplied as two 5-mL clear neutral glass (Type 1) syringe barrels, eachcontaining a 250 mg/5 mL (50 mg/mL) solution for intramuscularinjection. Upon receipt, FASLODEX™ was stored refrigerated (2°-8° C.)and protected from light. The procedure to prepare and administerFASLODEX™ was performed as outlined in the manufacturer's prescribinginformation.

Lyophilized pharmaceutical compositions of formulations F005g5, F005H3,F015a3, Lot 15, Lot 26, Lot 27, Lot 28, Lot 42, Lot 43, Lot 45, Lot 46,Lot 47, and Lot 48 were reconstituted prior to dosing. Using an emptysyringe and hypodermic needle, about 5 mL of air was withdrawn from thehead space of the vial (above the lyophilized contents) via the septumand the syringe and needle were discarded. Using a sterile syringe andhypodermic needle, 5 mL of sterile water for injection, USP were addedto the vial by piercing the septum and injecting a stream of waterslowly around the inner wall of the neck of the vial to wet thelyophilized cake without touching any of the vial contents. The needlewas removed from the septum and the vial was gently swirled until avisually homogeneous particulate suspension formed, with no visualclumps or material attached to the inside wall of the vial. If ahomogeneous suspension was not formed after 5 minutes of swirling, thevial was vortexed until a homogeneous suspension was formed. The vialswere not shaken to avoid generating bubbles or excessive foam.

Group 18 was administered an intravenous batch of fulvestrant (batchFV-004/15M) prepared as follows by (% w/v): 2% fulvestrant, 10% EtOH,79% propylene glycol, 1% Poloxamer 407, 8% Water for Injection, USP.Fulvestrant API was stored at 2-8° C., protected from light. Care wastaken to protect the API from humidity during weighing. Fulvestrantpowder was dissolved in ethanol and swirled and vortexed as needed todissolve completely. Propylene glycol was added and mixed to dissolve toa clear liquid state. Poloxamer 407 was dissolved in water forinjection, USP in a separate vessel and mixed, vortexed, and sonicatedas needed to dissolve into to a clear liquid state. The Poloxamer 407 inwater for injection solution was added to the fulvestrant/ethanolsolution. Propylene glycol was added and the solution was mixed andvortexed to achieve a clear liquid. The solution was filtered through a0.2 μm or 0.22 μm syringe (to ensure that all liquid volume was usable)tip filter (PVDF) into a clear glass vessel. The prepared formulation asstored at room temperature for up to four hours prior to dosing underprotection from light exposure. Intravenous doses were administered viathe cephalic (or other suitable) vein as a slow injection overapproximately 1 minute. Batch FV-004/15M was administered intravenouslyat a dose of 2.5 mg/kg.

The animals were not fasted prior to dosing. Each animal in Groups 4-9,11-17, and 19-48 received a single intramuscular (IM) dose of only oneof the appropriate test article pharmaceutical compositions as outlinedin Table 39. IM doses were administered with a 20 G needle via bolusinjection into the same large muscle mass (using the Z-track injectiontechnique) in the left hind limb of each animal. Attempts were made forconsistent injections between animals [selection of the dose site(muscle), depth, etc.]. The hair was clipped from the injection siteprior to dosing. The injection site was marked following dosing andremarked as necessary throughout the study. Specifications for all dosedelivery were recorded and reported in the study report [including, butnot limited to needle gauge/length, syringe size/barrel type withmanufacturer and part number, estimated injection depth into the muscle,approximate duration required to administer the injection; anysubstantial resistance (either flow through the syringe/needle and/orinto the muscle during administration)] was documented. Animals inGroups 13-17 and 19-48 were administered 1 tablet or capsule (25 mg) of(PO) diphenhydramine at approximately 1 hour prior to dosing.

All animals were observed at least twice a day for morbidity, mortality,injury, and availability of food and water. Any animals in poor healthwere identified for further monitoring and possible euthanasia.

Whole venous blood samples of approximately 2 mL each were collectedfrom a peripheral vein of all animals for determination of fulvestrantexposure. Blood samples for Groups 1-7 were collected predose and at0.25, 0.5, 1, 2, 4, 8, and 12 (on Day 1); and 24 (on Day 2), 48 (on Day3), 72 (on Day 4), 96 (on Day 5), 120 (on Day 6), 192 (on Day 9), 264(on Day 12), 336 (on Day 15), 384 (on Day 17), 528 (on Day 23), and 672(on Day 29) hours postdose. Blood samples for Groups 8-14 were collectedpredose and at 0.25, 0.5, 1, 2, 4, 8, and 12 (on Day 1); and 24 (on Day2), 48 (on Day 3), 72 (on Day 4), 96 (on Day 5), 120 (on Day 6), 192 (onDay 9), 264 (on Day 12), 336 (on Day 15), 384 (on Day 17), 456 (on Day20), 528 (on Day 23), 600 (on Day 26), 672 (on Day 29), 696 (Day 30),768 (Day 33), 816 (Day 35), 864 (Day 37), 936 (Day 40) and 1008 (Day 43)hours post-dose. Blood samples for Groups 15-17 and 19-21 were collectedpredose and at 0.25, 0.5, 1, 2, 4, 8, 12 (Day 1), 24 (Day 2), 48 (Day3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 192 (Day 9), 264 (Day 12), 336(Day 15), 384 (Day 17), 456 (Day 20), 528 (Day 23), 600 (Day 26), 672(Day 29), 696 (Day 30), 768 (Day 33), 816 (Day 35), 864 (Day 37), 936(Day 40), 1008 (Day 43), and 1176 (Day 50) hours postdose. Blood samplesfor Group 18 were collected predose and at 0.033 (2 minutes), 0.1 (6minutes), 0.13 (8 minutes), 0.27 (16 minutes), 0.52 (31 minutes), 0.77(46 minutes), 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose on Day 1 andat 24 (on Day 2), 30 (on Day 2), 48 (on Day 3) and 72 (on Day 4) hourspostdose, with postdose measurements from the start of doseadministration, which took about 1 minute to complete. Blood samples forGroups 22-48 were collected predose and at 0.25, 0.5, 1, 2, 4, 8, 12(Day 1), 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6),144 (Day 7), 168 (Day 8), 192 (Day 9), 216 (Day 10), 240 (Day 11), 264(Day 12), 336 (Day 15), 384 (Day 17), 456 (Day 20), 528 (Day 23), 600(Day 26), 672 (Day 29), 696 (Day 30), 768 (Day 33), 816 (Day 35), 864(Day 37), 936 (Day 40), 1008 (Day 43), and 1176 (Day 50) hours postdose.Blood was collected with sodium heparin anticoagulant (glass tube, nogel separator). All blood samples were placed on wet ice followingcollection until centrifuged. Blood was centrifuged at 3500 rpm for 7minutes at 2 to 8° C. Plasma (minimum of 0.8 mL volume) was separatedfrom blood cells within 0.75 hours of blood collection and frozen.Plasma samples were initially placed on dry ice prior to being stored inthe appropriate freezer (−60 to −90° C.). Samples were shipped on dryice for bioanalytical analysis to determine absolute ng/mL fulvestrantin the plasma.

TABLE 40 PK parameters compared to Faslodex lots based upon the nominaldose 15.4 mg/kg AUC_(0-14 d) AUC_(0-28 d) Formulation PK parametersbased upon the Cmax ratio ratio (Geometric Mean, nominal dose 15.4 mg/kgratio to to to n = 3 unless indicated Cmax AUC_(0-14 d) AUC_(0-28 d)Faslodex Faslodex Faslodex otherwise) (ng/mL) (hr * ng/mL) (hr * ng/mL)(%) (%) (%) Faslodex (All, n = 22) 37.5 7408 9195 100 100 100 F005g532.1 6950 10400 86 94 113 Lot 15, by Process E1 20.1 3890 5500 54 53 60Lot 15, by Process E2 20.3 4190 6230 54 57 68 Lot 26, by Process F1 19.54150 6650 52 56 72 Lot 26, by Process F2 30.5 5510 7850 81 74 85 Lot 26,by Process F3 25.7 5350 8260 68 72 90 Lot 26, by Process F4 30.8 721010200 82 97 111 Lot 26, by Process J1 25.2 5490 7910 67 74 86 Lot 26, byProcess J2 20.8 4640 7190 55 63 78 Lot 26, by Process J3 21.1 4720 731056 64 80 Lot 26, by Process J4 21.3 4320 5900 57 58 64 Lot 42, byProcess G1 28.1 4640 7410 75 63 81 Lot 42, by Process G2 33.8 6110 880090 82 96 Lot 43, by Process H1 25.0 5190 7500 67 70 82 Lot 43, byProcess H2 22.2 4430 6250 59 60 68 Lot 27, by Process A1 92.6 6150 8710247 83 95 Lot 27, by Process A2 27.9 6240 9170 74 84 100 Lot 27, byProcess A3 26.3 5100 7680 70 69 84 Lot 27, by Process A4 29.1 6030 862078 81 94 Lot 28, by Process B1 21.9 3950 6230 58 53 68 Lot 28, byProcess B2 36.3 7010 9870 97 95 107 Lot 28, by Process B3 31.6 6880 966084 93 105 Lot 28, by Process B4 31.0 6330 9000 83 85 98 Lot 45, byProcess C1 29.8 5320 8560 79 72 93 Lot 46 30.2 5570 8240 80 75 90 Lot 4727.9 5230 8070 74 71 88 Lot 48 26.3 4900 7410 70 66 81

A model independent method was used to determine C_(max) and AUC valuesfrom fulvestrant plasma concentration-time data. Results are shown inTables 31-37 and 40 and FIGS. 1A, 1B, 2A, 2B, 2C, 13, and 14. Table 31shows the pharmacokinetic data from the 15.4 mg/kg dosages as nominallydosed (based on the target fulvestrant concentration for eachpharmaceutical composition). An “Assay %” is shown in Table 31 for thefulvestrant pharmaceutical compositions of the present disclosure usedin the study. The “Assay %” represents the percentage equivalence of theparticular pharmaceutical composition in comparison to the FASLODEX™label claim fulvestrant concentration, with “Assay %” values determinedvia HPLC, measurement samples taken pre- and post-dose, with one valueselected for normalization. The data in Tables 32-37 are normalizedusing the “Assay %” values to compare PK results based upon the actualmg/kg of fulvestrant administered, assuming linear scaling. FIGS. 1A,1B, 2A, 2B, and 2C depict graphs of the dose normalized fulvestrant meanplasma concentrations. Table 40 shows the pharmacokinetic data from the15.4 mg/kg dosages as nominally dosed (based on the target fulvestrantconcentration for each pharmaceutical composition) in comparison to thegeometric mean of all Faslodex lots tested (n=22). FIGS. 13 and 14depict fulvestrant plasma measurements for administration of FaslodexLot MB948 to three female dogs and administration of fulvestrantformulation Lot 27 processed by Process A2 to three female dogs(referred to in FIG. 14 as subjects 924, 925, and 926).

Example: Microscopic Imaging of Fulvestrant Particles in Suspensions

Some exemplary fulvestrant pharmaceutical compositions of the presentdisclosure were examined via optical and scanning electron microscopy.Suspensions of fulvestrant pharmaceutical compositions Variants B, E, I,J, K, L, L3F, L6, F003a, F003b, F004a, F003e, F00k2, and F003k3 wereexamined via optical microscopy. Optical microscopy was performed at400× magnification with a polarized light filter using fully dispersedhomogeneous suspension samples.

Example: Particle Size Distribution Characterization of FulvestrantPharmaceutical Compositions

Batches of fulvestrant pharmaceutical composition Lot 27, describedelsewhere herein, were prepared by the methods of preparation 101 ofFIG. 15. Samples were taken periodically during high shear mixing, priorto any high pressure homogenization steps. Some test samples, referredto as “Sample 1”, were taken after approximately five hours of highshear mixing and other test samples, referred to as “Sample 2”, weretaken after approximately 13.7 hours to high shear mixing. Particlesizes of test samples were analyzed using optical microscopy with aMalvern Morphologi G3 apparatus for microscopy image capture andanalysis. CE diameters were measured and number-weighted andvolume-weighted particle size distribution parameters were determined asshown in Tables 41 and 42. The CE diameter ranges of measurementaliquots are also shown, with the lower range value of 0.54 micronsrepresenting the lower limit of detection for the apparatus setup. Testsamples were analyzed with a Malvern Mastersizer 3000 apparatus forlaser diffraction particle size characterization of LD diameters.

TABLE 41 Volume-Weighted Distribution Parameters Circle CE CE EquivalentDv Dv CE (CE)- LD LD LD (10) (50) Dv (90) diameter- Dv10 Dv50 Dv90Formulation (μm) (μm) (μm) range (μm) (μm) (μm) (μm) Lot 27 6.113 13.7732.71 0.54-49.72 1.81 6.68 16.6 (Sample 1) Lot 27 6.509 14.34 28.640.54-54.14 1.85 6.93 17.7 (Sample 1) Lot 27 6.378 12.76 23.90 0.54-55.04(Sample 1) Lot 27 5.297 10.73 24.57 (Sample 1) Lot 27 6.015 13.03 25.25(Sample 1) Lot 27 5.446 11.41 22.10 (Sample 1) Lot 27 7.222 14.93 28.99(Sample 1) Lot 27 8.747 18.31 32.93 (Sample 1) Lot 27 7.663 14.96 26.58(Sample 1) Lot 27 6.733 13.61 24.70 0.54-42.64 1.96 7.54 19.3 (Sample 2)Lot 27 7.182 14.12 25.15 0.54-44.65 (Sample 2) Lot 27 6.920 13.26 22.630.54-38.24 (Sample 2) Lot 27 7.400 14.86 27.82 (Sample 2) Lot 27 6.85714.08 27.39 (Sample 2) Lot 27 8.117 16.58 30.90 (Sample 2)

TABLE 42 Number-Weighted Distribution Parameters Circle Equivalent (CE)-CE Dn10 CE Dn50 CE Dn90 diameter- Formulation (μm) (μm) (μm) range (μm)Lot 27 (Sample 1) 1.10 3.92 8.91 0.54-49.72 Lot 27 (Sample 1) 1.14 4.069.61 0.54-54.14 Lot 27 (Sample 1) 0.95 4.16 9.85 0.54-55.04 Lot 27(Sample 2) 1.08 4.24 10.34 0.54-42.64 Lot 27 (Sample 2) 0.85 3.71 10.520.54-44.65 Lot 27 (Sample 2) 0.91 4.07 10.55 0.54-38.24

Example: Particle Size Distribution Characterization of FulvestrantPharmaceutical Compositions

Fulvestrant pharmaceutical compositions F005g5, Lot 27, Lot 28, and Lot45, described elsewhere herein, were prepared by the methods ofpreparation shown schematically as process 101 of FIG. 15. Samples ofeach Lot were prepared using different processes as indicated in Tables43 to 50 to achieve fulvestrant particle sizes and particle sizedistributions. The preparation processes are referred to withalphanumeric identifiers, such as “Process A1,” “Process A2,” and thelike, with each process representing a set offulvestrant-particle-size-reduction steps, as more fully describedelsewhere herein, to achieve final fulvestrant particle size andparticle size distributions as shown in the Tables 43 to 50. Testsamples were evaluated for particle size both prior to drying vialyophilization, which are indicated as “(100× Suspensions)”, and afterlyophilization and reconstitution, which are indicated as “(100×Reconstituted Suspensions)” in the Tables 43 to 50. Samples wereanalyzed with a Malvern Morphologi G3 apparatus for microscopy imagecapture and analysis. CE diameters were measured and volume-weightedparticle size distribution parameters were determined. The CE diameterranges of measurement samples are also shown, with the lower range valueof 0.54 microns representing the lower limit of detection for theapparatus setup. Samples were analyzed with a Malvern Mastersizer 3000apparatus for laser diffraction particle size characterization of LDdiameters.

TABLE 43 Volume-Weighted Distribution Parameters (100x ReconstitutedSuspensions) Circle Equivalent CE CE CE (CE)- Dv10 Dv50 Dv90 diameter-Formulation Process (μm) (μm) (μm) range (μm) Lot 27 Process 6.606 16.1436.36 0.54-59.46 A1 Process 7.031 31.23 84.50 0.54-107.10 A2 Process6.725 24.83 53.11 0.54-84.16 A3 Process 6.790 43.74 98.32 0.54-105.94 A4Lot 28 Process 5.333 17.64 41.18 0.54-53.33 B1 Process 4.863 12.71 42.290.54-75.19 B2 Process 5.376 15.85 49.64 0.54-75.62 B3 Process 4.14425.86 82.19 0.54-107.08 B4 Lot 45 Process 8.904 35.32 66.41 0.54-85.05C1 Process 8.135 34.79 56.77 0.54-81.50 C2

TABLE 44 Volume-Weighted Distribution Parameters (100x ReconstitutedSuspensions) Circle Equivalent As-Is Sonicated CE CE CE (CE)- LD LD LDLD LD LD Dv10 Dv50 Dv90 diameter- Dv10 Dv50 Dv90 Dv10 Dv50 Dv90Formulation Process (μm) (μm) (μm) range (μm) (μm) (μm) (μm) (μm) (μm)(μm) Lot 45 Process 5.140 14.44 42.62 0.54-71.31 3.42 8.21 33.8 2.815.57 10.6 C9 Lot 45 Process 6.558 17.10 44.70 0.54-74.57 3.37 7.81 32.62.82 5.58 10.5 C9 Lot 45 Process 6.648 19.97 56.47 0.54-112.57 3.50 9.3443.1 2.81 5.57 10.5 C9 Lot 45 Process 6.541 15.68 37.75 0.54-55.93 3.207.08 24.3 2.80 5.52 10.7 C10 Lot 45 Process 5.787 13.11 32.25 0.54-55.823.33 7.83 33.9 2.98 5.80 11.1 C10 Lot 45 Process 5.375 14.59 55.020.54-88.17 3.38 8.02 35.6 2.97 5.79 11.1 C10 F005g5 As 3.07 29.2 95.12.20 5.25 14.0 shown in Table 34

TABLE 45 Volume-Weighted Distribution Parameters (100x ReconstitutedSuspensions) Circle Equivalent CE (CE)- Dv10 CE Dv50 CE Dv90 diameter-Formulation Process (μm) (μm) (μm) range (μm) Lot 27 Process A2 4.54711.10 33.19 0.54-55.75 Lot 27 Process A2 4.290 10.15 23.66 0.54-49.72Lot 27 Process A2 5.908 12.98 25.55 0.54-42.63 Lot 27 Process A2 6.07512.81 23.11 0.54-47.71 Lot 27 Process A2 7.022 15.59 30.94 0.54-69.41Lot 27 Process A2 5.399 12.22 34.36 0.54-51.56 Lot 27 Process A13 4.8911.84 32.47 Lot 27 Process A13 6.46 15.33 32.47 Lot 27 Process A13 4.9311.90 31.23 Lot 27 Process A13 5.54 14.17 50.26 Lot 27 Process A13 4.1910.16 32.22 Lot 27 Process A13 5.91 13.71 33.81 Lot 27 Process A13 5.1013.26 45.32 Lot 27 Process A13 4.61 11.47 39.79 Lot 27 Process A13 4.7912.50 46.19 Lot 27 Process A13 4.71 10.33 22.64 Lot 27 Process A13 5.6612.66 29.72 Lot 27 Process A13 4.96 11.62 37.81 Lot 27 Process A13 4.2212.46 42.59 Lot 27 Process A13 5.80 19.69 57.80 Lot 27 Process A13 5.1211.53 28.37 Lot 27 Process A13 3.84 9.28 32.42 Lot 27 Process A13 4.6410.32 25.28 Lot 27 Process A13 4.86 11.69 32.44

TABLE 46 Volume-Weighted Distribution Parameters (100x ReconstitutedSuspensions) As-Is Sonicated LD LD LD LD LD Dv10 Dv50 Dv90 Dv10 LD Dv50Dv90 Formulation Process (μm) (μm) (μm) (μm) (μm) (μm) Lot 27 Process2.03 8.41 36.0 1.20 3.93 7.97 A13 Lot 27 Process 1.96 7.83 35.0 1.143.69 7.57 A13 Lot 27 Process 2.08 9.14 41.3 1.20 3.92 7.94 A13 Lot 27Process 2.10 9.65 40.3 1.15 3.66 7.53 A13 Lot 27 Process 1.67 6.10 26.51.08 3.42 7.19 A13 Lot 27 Process 1.70 5.71 21.6 1.17 3.80 7.78 A13 Lot27 Process 2.53 15.8 48.4 1.27 4.07 8.72 A13 Lot 27 Process 2.01 12.657.6 1.01 3.04 6.85 A13 Lot 27 Process 1.62 6.34 29.5 0.96 2.76 5.89 A13

TABLE 47 Volume-Weighted Distribution Parameters (100x Suspensions)Circle Equivalent CE (CE)- Dv10 CE Dv50 CE Dv90 diameter- FormulationProcess (μm) (μm) (μm) range (μm) Lot 27 Process A15 5.199 10.4 17.520.54-27.89 Process A16 3.766 7.411 12.15 0.54-25.43 Process A17 3.0536.256 10.81 0.54-38.27 Process A18 3.727 7.277 13.91 0.54-31.30 Lot 28Process B5 4.442 8.585 15.04 0.54-41.23 Process B6 4.134 7.773 13.250.54-22.59 Process B7 3.835 7.311 13.11 0.54-25.94 Process B8 3.4176.644 11.62 0.54-28.25 Lot 45 Process C3 7.160 14.79 25.70 0.54-47.55Process C4 8.587 18.15 36.68 0.54-62.10

TABLE 48 Volume-Weighted Distribution Parameters (100x Suspensions)As-Is Sonicated LD LD LD LD LD Dv10 Dv50 LD Dv90 Dv10 Dv50 Dv90Formulation Process (μm) (μm) (μm) (μm) (μm) (μm) Lot 27 Process 1.083.29 7.68 0.91 2.62 6.98 A15 Process 1.03 3.15 7.00 0.83 2.32 5.72 A16Process 0.97 2.96 6.52 0.78 2.13 5.01 A17 Process 0.92 2.91 6.32 0.721.96 4.38 A18 Lot 45 Process 1.50 6.03 12.0 0.83 2.30 5.69 C3 Process1.59 5.82 11.0 0.85 2.37 5.74 C4

TABLE 49 Volume-Weighted Distribution Parameters (100x Suspensions)Circle Equivalent As-Is Sonicated CE CE CE (CE)- LD LD LD LD LD LD Dv10Dv50 Dv90 diameter- Dv10 Dv50 Dv90 Dv10 Dv50 Dv90 Formulation Process(μm) (μm) (μm) range (μm) (μm) (μm) (μm) (μm) (μm) (μm) Lot 45 Process12.320 29.88 57.24 0.54-90.58 1.51 5.40 10.7 0.80 2.11 4.64 C3 Lot 45Process 7.454 17.37 40.29 0.54-76.61 1.71 6.36 12.5 0.82 2.26 5.20 C4Lot 45 Process 12.130 27.59 50.08 0.54-87.69 1.73 6.38 12.7 0.79 2.154.77 C5 Lot 45 Process 8.193 17.89 35.05 0.54-54.50 1.63 5.85 11.7 0.792.13 4.68 C5 Lot 45 Process 8.690 19.36 35.53 0.54-64.77 1.70 6.12 12.00.77 2.05 4.45 C5 Lot 45 Process 8.218 17.00 46.80 0.54-80.21 1.46 4.929.59 1.36 4.71 9.55 C6 Lot 45 Process 6.455 14.94 38.47 0.54-65.55 1.274.21 8.61 0.77 2.11 4.66 C7 Lot 45 Process 7.795 17.20 31.60 0.54-45.031.55 5.37 10.7 0.77 2.14 4.81 C8 Lot 45 Process 9.257 20.16 39.470.54-84.26 1.64 5.64 11.2 0.78 2.19 4.99 C8 Lot 45 Process 10.050 21.3536.43 0.54-59.43 1.59 5.55 11.1 0.76 2.10 4.66 C8

TABLE 50 Volume-Weighted Distribution Parameters (100x Suspensions)Circle Equivalent As-Is As-Is As-Is CE CE CE (CE)- LD LD LD Dv10 Dv50Dv90 diameter- Dv10 Dv50 Dv90 Formulation Process (μm) (μm) (μm) range(μm) (μm) (μm) (μm) Lot 27 Process A5 5.506 12.94 26.24 0.54-52.71 1.545.70 11.3 Lot 27 Process A6 8.740 19.30 35.62 0.54-54.43 1.42 5.10 10.1Lot 27 Process A7 7.862 18.92 36.09 0.54-52.63 1.48 5.30 10.4 Lot 27Process A8 8.184 17.49 33.02 0.54-63.56 1.46 5.04 9.69 Lot 27 Process A97.451 15.99 29.94 0.54-55.58 1.49 5.00 9.65 Lot 27 Process A10 7.67318.50 36.71 0.54-74.22 1.59 5.55 10.6 Lot 27 Process A11 9.093 20.0145.26 0.54-61.26 1.72 6.11 12.1 Lot 27 Process A12 6.355 14.92 46.310.54-63.98 1.66 5.77 10.9 Lot 27 Process A13 7.029 15.66 31.060.54-55.89 1.07 3.51 7.32 Lot 27 Process A14 7.870 20.15 43.790.54-62.35 1.74 5.87 11.0 Lot 27 Process A14 8.499 19.06 37.900.54-70.88 1.67 5.49 10.5 Lot 27 Process A14 8.072 17.43 30.900.54-56.50 1.76 6.01 11.5 Lot 27 Process A14 8.078 18.98 45.320.54-69.82 1.81 6.43 12.5

When ranges are used herein for chemical or physical properties, such asparticle size or particle size distribution, formulation componentconcentrations, or pharmacokinetic properties, all combinations, andsubcombinations of ranges for specific embodiments therein are intendedto be included.

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, in its entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A suspension comprising fulvestrant particles and a vehicle; whereinoptionally the fulvestrant particles have an LD Dv(10) between about 1micron to about 3 microns, preferably an LD Dv(10) of about 1-2 microns,an LD Dv(50) between about 2 microns and about 35 microns, preferably anLD Dv(50) of about 2-4 microns, and an LD Dv(90) between about 4 micronsand about 120 microns, preferably an LD Dv(90) of about 6-9 microns,and; wherein optionally the vehicle is a non-oil vehicle, preferablywater or non-aqueous vehicle; wherein optionally fulvestrant is at aconcentration of about 100 mg/mL; and wherein optionally the suspensionis substantially oil-free.
 2. A suspension comprising fulvestrant and avehicle, wherein the fulvestrant is at a concentration equal to orgreater than about 50 mg/mL, preferably about 50 mg/mL or about 100mg/mL; wherein optionally the vehicle is a non-oil vehicle, preferablywater or non-aqueous vehicle; wherein optionally the suspension issubstantially oil-free.
 3. A pharmaceutical composition comprisingfulvestrant particles and a non-oil vehicle, wherein optionally thepharmaceutical composition further comprises at least one stabilizerselected from the group consisting of surfactants, polymers,cross-linked polymers, buffering agents, electrolytes, andnon-electrolytes, preferably wherein the at least one stabilizer is across-linked polymer, preferably carboxymethylcellulose sodium, or theat least one stabilizer is selected from: the group of polyethyleneoxide (PEO), a PEO derivative, polysorbate 80, polysorbate 20, poloxamer188, poloxamer 124, poloxamer 407, polyethoxylated vegetable oils,polyethoxylated castor oil, sorbitan palmitate, lecithin, poly(vinylalcohol), human serum albumin, and mixtures thereof, the groupconsisting of polyvinylpyrrolidone, povidone K12, povidone K17,PLASDONE™ C-12 povidone, PLASDONE™ C-17 povidone, PLASDONE™ C-30povidone, polyethylene glycol 3350, and mixtures thereof, the groupconsisting of sodium chloride, calcium chloride, and mixtures thereof,or the group consisting of dextrose, glycerol, mannitol, and mixturesthereof; wherein optionally the pharmaceutical composition furthercomprises at least one buffering agent selected from the groupconsisting of NaH₂PO₄.H₂O, NaH₂PO₄.2H₂O, anhydrous NaH₂PO₄, sodiumcitrate, citric acid, Tris, sodium hydroxide, HCl, or a mixture thereof;and wherein optionally the pharmaceutical composition further comprisessolubilized fulvestrant.
 4. A pharmaceutical composition comprisingfulvestrant particles, wherein the fulvestrant particles have one ormore of: an LD Dv(10) between about 1 micron to about 3 microns,preferably between about 1 micron to about 2 microns or between about 2microns and about 3 microns; an LD Dv(50) between about 2 microns andabout 35 microns, preferably between about 2 microns to about 6 microns,more preferably between about 2 microns and about 4 microns; and an LDDv(90) between about 4 microns and about 120 microns, preferably betweenabout 7 microns to about 15 microns, more preferably between about 12microns to about 14 microns or between about 9 microns to about 11microns, or preferably between about 6 microns and about 9 microns, morepreferably between about 6 microns and about 8 microns, most preferablybetween about 7 microns and about 8 microns; wherein optionally thepharmaceutical composition is in the form of a suspension, preferably anaqueous suspension.
 5. A pharmaceutical composition comprisingfulvestrant, wherein the fulvestrant is at a concentration of about 100mg/mL and wherein upon administration to a subject, the 90% confidenceintervals (CI) of the relative mean AUC_((0-t)) and AUC_((0-∞)) offulvestrant of the pharmaceutical composition is within 80% to 125% ofthe relative mean AUC_((0-t)) and AUC_((0-∞)), respectively, offulvestrant upon administration of a reference listed fulvestrantproduct, for example, FASLODEX™; wherein optionally the reference listedfulvestrant product comprises fulvestrant at a concentration of about 50mg/mL; wherein optionally upon administration to a subject, the 90%confidence intervals (CI) of the relative mean Cmax of fulvestrant iswithin 40% to 80% of the relative mean Cmax of fulvestrant afteradministration of the reference listed fulvestrant product.
 6. Apharmaceutical composition comprising fulvestrant wherein thefulvestrant is at a concentration of about 100 mg/mL and wherein afteran initial administration to a subject of the pharmaceutical compositioncomprising 500 mg fulvestrant on day 1 and an additional administrationof the pharmaceutical composition comprising 500 mg fulvestrant on day15 to the subject provides: an AUC in the range of 9,120-14,250 ng·hr/mLof fulvestrant; wherein optionally the pharmaceutical composition isadministered as a single injection of about 5 mL or administered as twoinjections of about 2.5 mL.
 7. A pharmaceutical composition comprisingfulvestrant particles wherein the fulvestrant is at a concentration ofabout 40 to about 125 mg/mL.
 8. The pharmaceutical composition of claim7, wherein at least about 70% of the fulvestrant is present asfulvestrant particles, preferably at least about 80% of the fulvestrantis present as fulvestrant particles, more preferably at least about 90%of the fulvestrant is present as fulvestrant particles.
 9. Thepharmaceutical composition of claim 7, wherein no more than about 20% ofthe fulvestrant is solubilized, preferably no more than about 10% of thefulvestrant is solubilized, more preferably no more than about 5% of thefulvestrant is solubilized.
 10. The pharmaceutical composition of claim6, wherein the fulvestrant particles: have one or more of: an LD Dv(10)between about 1 micron to about 3 microns; an LD Dv(50) between about 2microns and about 35 microns; and an LD Dv(90) between about 4 micronsand about 120 microns; have one or more of: an LD Dv(10) between about1-2 microns; an LD Dv(50) between about 2-4 microns; and an LD Dv(90)between about 6-9 microns; have an LD Dv(90) of about 12-14 microns;have an LD Dv(90) of about 9-11 microns; have an LD Dv(90) of about 6-9microns; have an LD Dv(90) of about 6-8 microns; or have an LD Dv(90) ofabout 7-8 microns.
 11. A method of forming an aqueous fulvestrantsuspension comprising: mixing an aqueous medium and at least onestabilizer to form a suspension vehicle, the at least one stabilizerpreferably comprising one surfactant and one polymer or one surfactantand one non-electrolyte; adding an amount of fulvestrant to thesuspension vehicle; and dispersing the fulvestrant in the suspensionvehicle to form the aqueous fulvestrant suspension, preferably performedusing high shear mixing; optionally further comprising homogenizing theaqueous fulvestrant suspension, the homogenizing preferably performedusing high pressure homogenization, preferably at a pressure of about15,000 psi to about 45,000 psi, the method preferably further comprisingadding an electrolyte to the homogenized aqueous fulvestrant suspensionand mixing the electrolyte into the suspension or adding anon-electrolyte to the homogenized aqueous fulvestrant suspension andmixing the non-electrolyte into the suspension; the method optionallyfurther comprising concentrating the fulvestrant suspension by phaseseparating the suspension and removing a portion of the supernatant; themethod optionally further comprising drying the aqueous suspension toform a dried pharmaceutical composition, the method preferably furthercomprising sterilizing the dried pharmaceutical composition using gammairradiation, the method more preferably further comprisingreconstituting the dried pharmaceutical composition into a secondaqueous suspension by adding at least one of water for injection (WFI),normal saline (NS), and 5% dextrose in water (D5W).
 12. An aqueousfulvestrant suspension prepared according to the method of claim
 11. 13.A pharmaceutical composition comprising the aqueous fulvestrantsuspension of claim 12, wherein optionally the pharmaceuticalcomposition comprises fulvestrant particles: having one or more of: anLD Dv(10) between about 1 micron to about 3 microns; an LD Dv(50)between about 2 microns and about 35 microns; and an LD Dv(90) betweenabout 4 microns and about 120 microns; having one or more of: an LDDv(10) between about 1-2 microns; an LD Dv(90) between about 6-9microns; and an LD Dv(50) between about 2-4 microns; having one or moreof: a CE Dv(90) between about 10 microns and about 200 microns; a CEDv(50) between about 5 microns and about 60 microns; and a CE Dv(10)between about 1 microns and about 25 microns; having a CE Dv(90) betweenabout 10 microns and about 200 microns; having a CE Dv(50) between about5 microns and about 60 microns; or having a CE Dv(10) between about 1microns and about 25 microns.
 14. An aqueous fulvestrant suspensioncomprising: an amount of fulvestrant, preferably about 500 mg, about 450mg, about 400 mg, about 350 mg, about 300 mg, or about 250 mg; about 0.2mg/mL to about 75 mg/mL of one or more stabilizers; and an amount ofaqueous medium; wherein upon administration of the aqueous fulvestrantsuspension to a subject in a single intramuscular injection, the 90%confidence intervals (CI) of the relative mean AUC(0-t) and AUC(0-∞) offulvestrant is within 80% to 125% of the relative mean AUC(0-t) andAUC(0-∞), respectively, of fulvestrant after administration of 500 mg offulvestrant in the form of FASLODEX™ administered intramuscularly as two5 mL injections; wherein optionally the suspension has a volume of about3.0 to about 5.0 mL, preferably about 3.5 to about 4.5 mL, morepreferably about 4.0 mL.
 15. The aqueous fulvestrant suspension of claim14, wherein the one or more stabilizers: is selected from the groupconsisting of surfactants, polymers, cross-linked polymers, bufferingagents, electrolytes, and non-electrolytes, is selected from the groupconsisting of polyethylene oxide (PEO), a PEO derivative, polysorbate80, polysorbate 20, poloxamer 188, poloxamer 124, poloxamer 407,polyethoxylated vegetable oils, polyethoxylated castor oil, sorbitanpalmitate, lecithin, poly(vinyl alcohol), human serum albumin, andmixtures thereof, is selected from the group consisting ofpolyvinylpyrrolidone, povidone K12, povidone K17, PLASDONE™ C-12povidone, PLASDONE™ C-17 povidone, PLASDONE™ C-30 povidone, polyethyleneglycol 3350, and mixtures thereof, is selected from the group consistingof sodium chloride, calcium chloride, and mixtures thereof, or isselected from the group consisting of dextrose, glycerol, mannitol, andmixtures thereof.
 16. The aqueous fulvestrant suspension of claim 14,wherein the one or more stabilizers comprises a cross-linked polymer,preferably carboxymethylcellulose sodium.
 17. The aqueous fulvestrantsuspension of claim 14, further comprising at least one buffering agentselected from the group consisting of NaH₂PO₄.H₂O, NaH₂PO₄.2H₂O,anhydrous NaH₂PO₄, sodium citrate, citric acid, Tris, sodium hydroxide,HCl, or mixtures thereof.
 18. The aqueous fulvestrant suspension ofclaim 14, wherein the fulvestrant particles: have one or more of: an LDDv(10) between about 1 micron to about 3 microns; an LD Dv(50) betweenabout 2 microns and about 35 microns; and an LD Dv(90) between about 4microns and about 120 microns; or have one or more of: an LD Dv(10)between about 1-2 microns; an LD Dv(50) between about 2-4 microns; andan LD Dv(90) between about 6-9 microns.
 19. The aqueous fulvestrantsuspension of claim 14, wherein the fulvestrant particles: have one ormore of: a CE Dv(10) between about 4-10 microns, a CE Dv(50) betweenabout 10-35 microns, and a CE Dv(90) between about 35-110 microns; haveone or more of: a CE Dv(10) between about 4-8 microns, a CE Dv(50)between about 10-25 microns, and a CE Dv(90) between about 25-60microns; or have one or more of: a CE Dv(10) between about 4-8 microns,a CE Dv(50) between about 10-20 microns, and a CE Dv(90) between about20-35 microns.
 20. The aqueous fulvestrant suspension of claim 14,wherein: the suspension comprises about 56 mg/mL to about 59 mg/mL ofone or more stabilizers; and the one or more stabilizers comprises:about 1.0 mg/mL to about 4.0 mg/mL of one or more polyvinylpyrrolidones;about 5.0 mg/mL of polysorbate 80; and about 50 mg/mL of mannitol; orwherein: the suspension comprises about 56.6 mg/mL to about 57.4 mg/mLof one or more stabilizers; and the one or more stabilizers comprises:about 1.6 mg/mL to about 2.4 mg/mL of one or more polyvinylpyrrolidones;about 5.0 mg/mL of polysorbate 80; and about 50 mg/mL of mannitol; orwherein the suspension comprises: about 1.6 mg/mL to about 2.4 mg/mL ofPLASDONE™ C-12 povidone, povidone K12, or a combination thereof; about5.0 mg/mL of polysorbate 80; and about 50 mg/mL of mannitol; or whereinthe suspension comprises: about 100 mg/mL fulvestrant; about 1.6 mg/mLof PLASDONE™ C-12 povidone, povidone K12, or a combination thereof;about 5.0 mg/mL of polysorbate 80; and about 50 mg/mL of mannitol; orwherein the suspension comprises: about 100 mg/mL fulvestrant; about 2.4mg/mL of PLASDONE™ C-12 povidone, povidone K12, or a combinationthereof; about 5.0 mg/mL of polysorbate 80; and about 50 mg/mL ofmannitol.
 21. The pharmaceutical composition of claim 6, wherein afterthe initial administration the additional administration provides: botha C_(max) in the range of 10.04-12.55 ng/mL of fulvestrant and an AUC inthe range of 9,120-14,250 ng·hr/mL of fulvestrant; both a C_(max) in therange of 12.55-15.06 ng/mL of fulvestrant and an AUC in the range of9,120-14,250 ng·hr/mL of fulvestrant; both a C_(max) in the range of15.06-17.57 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250ng·hr/mL of fulvestrant; both a C_(max) in the range of 17.57-20.08ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 10.04-11.295 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 11.295-12.55 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 12.55-13.805 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 13.805-15.06 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 15.06-16.315 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 16.315-17.57 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 17.57-18.825 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 18.825-20.08 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 15.06-18.825 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; both a C_(max) in the range of 12.55-18.825 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant; or both a C_(max) in the range of 10.04-15.06 ng/mL offulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL offulvestrant.
 22. The pharmaceutical composition of claim 3, wherein thefulvestrant particles: have one or more of: a CE Dv(90) between about 35microns and about 110 microns; a CE Dv(50) between about 10 microns andabout 35 microns; and a CE Dv(10) between about 4 microns and about 10microns; have one or more of: a CE Dv(90) between about 25 microns andabout 60 microns; a CE Dv(50) between about 10 microns and about 25microns; and a CE Dv(10) between about 4 microns and about 8 microns;have one or more of: a CE Dv(90) between about 20 microns and about 35microns; a CE Dv(50) between about 10 microns and about 20 microns; anda CE Dv(10) between about 4 microns and about 8 microns; have one ormore of: a CE Dv(90) between about 30 microns and about 100 microns; aCE Dv(50) between about 10 microns and about 50 microns; and a CE Dv(10)between about 4 microns and about 10 microns; have one or more of: a CEDv(90) between about 50 microns and about 100 microns; a CE Dv(50)between about 20 microns and about 50 microns; and a CE Dv(10) betweenabout 6 microns and about 8 microns; have one or more of: a CE Dv(90)between about 50 microns and about 75 microns; a CE Dv(50) between about30 microns and about 40 microns; and a CE Dv(10) between about 8 micronsand about 10 microns; have one or more of: a CE Dv(90) between about 20microns and about 60 microns; a CE Dv(50) between about 9 microns andabout 20 microns; and a CE Dv(10) between about 3 microns and about 7microns; have one or more of: a CE Dv(90) between about 20 microns andabout 50 microns; a CE Dv(50) between about 9 microns and about 20microns; and a CE Dv(10) between about 3 microns and about 7 microns;have one or more of: a CE Dv(90) between about 20 microns and about 45microns; a CE Dv(50) between about 9 microns and about 20 microns; and aCE Dv(10) between about 3 microns and about 7 microns; have one or moreof: a CE Dv(90) between about 20 microns and about 40 microns; a CEDv(50) between about 9 microns and about 15 microns; and a CE Dv(10)between about 3 microns and about 7 microns; have one or more of: a CEDv(90) between about 20 microns and about 35 microns; a CE Dv(50)between about 9 microns and about 15 microns; and a CE Dv(10) betweenabout 3 microns and about 7 microns; have one or more of: a CE Dv(90)between about 20 microns and about 45 microns; a CE Dv(50) between about9 microns and about 15 microns; and a CE Dv(10) between about 3 micronsand about 7 microns; have a CE Dv(90) between about 10 microns and about200 microns; have a CE Dv(50) between about 5 microns and about 60microns; have a CE Dv(10) between about 1 microns and about 25 microns;have one or more of: a CE Dv(90) between about 10 microns and about 200microns; a CE Dv(50) between about 5 microns and about 60 microns; and aCE Dv(10) between about 1 microns and about 25 microns; have one or moreof: a CE Dv(90) between about 10 microns and about 200 microns; and a CEDv(50) between about 5 microns and about 60 microns; have one or moreof: a CE Dv(50) between about 5 microns and about 60 microns; and a CEDv(10) between about 1 microns and about 25 microns; or have one or moreof: a CE Dv(90) between about 10 microns and about 200 microns; and a CEDv(10) between about 1 microns and about 25 microns.
 23. The aqueousfulvestrant suspension of claim 14, wherein: upon administration of theaqueous fulvestrant suspension to a subject in a single intramuscularinjection, the 90% confidence intervals (CI) of the relative mean Cmaxof fulvestrant is within 40% to 80% of the relative mean Cmax offulvestrant after administration of 500 mg of fulvestrant in the form ofFASLODEX™ administered intramuscularly as two 5 mL injections; uponadministration of the aqueous fulvestrant suspension to a subject in asingle intramuscular injection, the 90% confidence intervals (CI) of therelative mean Cmax of fulvestrant is within 60% to 80% of the relativemean Cmax of fulvestrant after administration of 500 mg of fulvestrantin the form of FASLODEX™ administered intramuscularly as two 5 mLinjections; upon administration of the aqueous fulvestrant suspension toa subject in a single intramuscular injection, the 90% confidenceintervals (CI) of the relative mean Cmax of fulvestrant is within 50% to75% of the relative mean Cmax of fulvestrant after administration of 500mg of fulvestrant in the form of FASLODEX™ administered intramuscularlyas two 5 mL injections; upon administration of the aqueous fulvestrantsuspension to a subject in a single intramuscular injection, the 90%confidence intervals (CI) of the relative mean Cmax of fulvestrant iswithin 40% to 50% of the relative mean Cmax of fulvestrant afteradministration of 500 mg of fulvestrant in the form of FASLODEX™administered intramuscularly as two 5 mL injections; upon administrationof the aqueous fulvestrant suspension to a subject in a singleintramuscular injection, the 90% confidence intervals (CI) of therelative mean Cmax of fulvestrant is within 50% to 60% of the relativemean Cmax of fulvestrant after administration of 500 mg of fulvestrantin the form of FASLODEX™ administered intramuscularly as two 5 mLinjections; upon administration of the aqueous fulvestrant suspension toa subject in a single intramuscular injection, the 90% confidenceintervals (CI) of the relative mean Cmax of fulvestrant is within 60% to70% of the relative mean Cmax of fulvestrant after administration of 500mg of fulvestrant in the form of FASLODEX™ administered intramuscularlyas two 5 mL injections; upon administration of the aqueous fulvestrantsuspension to a subject in a single intramuscular injection, the 90%confidence intervals (CI) of the relative mean Cmax of fulvestrant iswithin 70% to 80% of the relative mean Cmax of fulvestrant afteradministration of 500 mg of fulvestrant in the form of FASLODEX™administered intramuscularly as two 5 mL injections; or uponadministration of the aqueous fulvestrant suspension to a subject in asingle intramuscular injection, the 90% confidence intervals (CI) of therelative mean Cmax of fulvestrant is within 70% to 80% of the relativemean Cmax of fulvestrant after administration of 500 mg of fulvestrantin the form of FASLODEX™ administered intramuscularly as two 5 mLinjections.
 24. A method of treating a subject having breast cancer,comprising administering to the subject the suspension of claim 1;wherein optionally the suspension, pharmaceutical composition, oraqueous fulvestrant suspension comprises about 50 mg/mL or about 100mg/mL fulvestrant; wherein optionally the suspension, pharmaceuticalcomposition, or aqueous fulvestrant suspension is administered incombination with one or more additional therapeutic agents, preferablypalbociclib.
 25. The method of claim 24, wherein the breast cancer ishormone receptor (HR)-positive breast cancer.
 26. The method of claim24, wherein the subject is a post-menopausal human woman with diseaseprogression following antiestrogen therapy.
 27. The method of claim 24,wherein the breast cancer is HR-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer.
 28. Themethod of claim 24, wherein the subject is a human woman with diseaseprogression after endocrine therapy.